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The finding that PHP can be acutely induced by pharmacological perturbation of glutamate receptors and not through reductions in calcium influx over rapid timescales may help to explain perplexing observations regarding the phenomenology of PhTx-mediated PHP. Although a reduction in calcium during these mEPSP events was discussed as a possible induction mechanism, estimates are that, at most, six mEPSP events occur per active zone during this induction time, a very low level and frequency of activity to reliably and robustly produce PHP expression.

Hence, pharmacological perturbation of postsynaptic glutamate receptors, rather than a reduction in calcium through these receptors, is an attractive mechanism to explain the characteristics of the acute induction of PHP by PhTx and raises interesting questions for future studies about how pharmacological receptor perturbation is transduced into PHP induction Goel, Why might a single retrograde signaling system exist to homeostatically stabilize synaptic strength at the Drosophila NMJ?

In central neurons, diverse forms of synaptic plasticity, including Hebbian and homeostatic, dynamically operate over multiple timescales to bi-directionally adjust synaptic strength. Further, translation-dependent and independent processes also contribute to retrograde homeostatic signaling in the hippocampus following AMPA receptor blockade. In contrast, the NMJ is built for stable excitation and is acutely sensitive to reductions in receptor function.

However, when neurotransmitter sensitivity in muscle is enhanced by increased receptor expression, no retrograde signaling system exists to homeostatically downregulate presynaptic efficacy. Thus, the muscle is endowed with multiple signaling systems to respond to perturbations but appears limited to signal retrograde increases in neurotransmitter release.

Hence, a single retrograde signaling system might provide an efficient means to ensure non-additive potentiation in synaptic strength and prevent hyper-excitation when conflicting signals and multiple inductive mechanisms are simultaneously activated Goel, The maintenance of synaptic homeostasis at the Drosophila neuromuscular junction is reversible and sensitive to high temperature Homeostasis is a vital mode of biological self-regulation. The hallmarks of homeostasis for any biological system are a baseline set point of physiological activity, detection of unacceptable deviations from the set point, and effective corrective measures to counteract deviations.

Homeostatic synaptic plasticity HSP is a form of neuroplasticity in which neurons and circuits resist environmental perturbations and stabilize levels of activity. One assumption is that if a perturbation triggers homeostatic corrective changes in neuronal properties, those corrective measures should be reversed upon removal of the perturbation. At the Drosophila NMJ, impairment of glutamate receptors causes a decrease in quantal size, which is offset by a corrective, homeostatic increase in the number of vesicles released per evoked presynaptic stimulus, or quantal content.

This process has been termed presynaptic homeostatic potentiation PHP. PHP was then reversed by halting expression of the dominant-negative receptor. The data show that PHP is fully reversible over a time course of h after the dominant-negative glutamate receptor stops being genetically expressed. These data suggest that a limitation of homeostatic signaling at high temperatures could stem from the synapse facing a combination of challenges simultaneously Yeates, Homeostasis is a strong form of biological regulation.

It permits individual cells or entire systems of cells to maintain core physiologic properties that are compatible with life. In the nervous system, decades of study have shown that while synapses and circuits are inherently plastic, they also possess robust homeostatic regulatory systems to maintain physiologic stability. Homeostatic plasticity in the nervous system is a non-Hebbian strategy to counteract challenges to neuronal function that may threaten to disrupt essential neuronal and circuit activities Turrigiano, Depending on the synaptic preparation examined and the environmental challenge presented to the synapse, homeostatic responses may be executed via compensatory adjustments to presynaptic neurotransmitter release Cull-Candy, ; Petersen, ; Murthy, ; Thiagarajan, ; Frank, ; Davis, , postsynaptic neurotransmitter receptor composition O'Brien, ; Turrigiano, ; Rongo , ; Turrigiano, , neuronal excitability Marder, ; Marder, ; Marder and Bucher, ; Bergquistet, ; Parrish, , or even developmentally, via changes in synaptic contact formation and maintenance Davis and Goodman, ; Burrone, ; Wefelmeyer, ; Yeates, and references therein.

Bidirectionality has been documented in several homeostatic systems, perhaps most prominently in the case of synaptic scaling of neurotransmitter receptors. For vertebrate neuronal culture preparations -- such as cortical neurons or spinal neurons—global silencing of network firing can induce increases in excitatory properties, such as increased AMPA-type glutamate receptor accumulation; by contrast, global enhancement of activity can induce the opposite type of response O'Brien, ; Turrigiano, ; Wierenga, ; Turrigiano, Bidirectionality is also a key feature underlying homeostatic alterations of neurotransmitter release at peripheral synapses such as the neuromuscular junction NMJ.

At the NMJs of Drosophila melanogaster and mammals, impairing neurotransmitter receptor function postsynaptically results in diminished sensitivity to single vesicles of transmitter. Electrophysiologically, this manifests as decreased quantal size. NMJs respond to this challenge by enhancing neurotransmitter vesicle release Cull-Candy, ; Plomp, , ; Petersen, ; Davis, ; Frank, By contrast, perturbations that enhance quantal size for example, overexpression of a vesicular neurotransmitter transporter in Drosophila can result in decreased quantal content Daniels, ; Gavino, ; Yeates, and references therein.

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Synapses and circuits possess myriad solutions to assume appropriate functional outputs in the face of perturbations Marder, ; Marder, Therefore, a corollary to bidirectional regulation is that homeostatic forms of regulation should also be reversible. There are experimental difficulties of presenting and removing a synaptic challenge in the context of a living synapse, so homeostatic reversibility has not been rigorously studied in an in vivo system or over extended periods of developmental time.

Understanding how homeostatic regulatory systems are reversibly turned on and off could have profound implications for elucidating fundamental properties of circuit regulation Yeates, This study exploits the Drosophila NMJ as a living synapse to test homeostatic reversibility. At the Drosophila NMJ, a canonical way to challenge synapse function is through glutamate receptor impairment Frank, , either genetically Petersen, or pharmacologically Frank, Impairments of muscle glutamate receptor function decrease quantal size. Decreased quantal size spurs muscle-to-nerve signaling that ultimately results in a homeostatic increase in presynaptic vesicle release, a process that has been termed presynaptic homeostatic potentiation PHP.

The most widely used experimental homeostatic challenges to Drosophila NMJ function are not easily reversed. These challenges include genetic deletion of the glutamate receptor subunit GluRIIA Petersen, and the mostly irreversible pharmacological inhibition of glutamate receptors with Philanthotoxin PhTox; Frank, ; Yeates, and references therein. For this study, a way was engineered to challenge NMJ function in vivo for significant periods of time, verify the effectiveness of the challenge at a defined developmental time point, remove the challenge, and then assess the homeostatic capacity of the NMJ at a later developmental time point.

In the course of conducting these studies, a high temperature limitation of homeostatic potentiation at the NMJ was uncovered Yeates, Thus study presents evidence that PHP at the Drosophila neuromuscular synapse is a reversible process. In doing so, prior findings were confirmed showing that there is a tight inverse relationship between quantal amplitude and QC at the NMJ.

Those findings were complemented with the results of temperature shift experiments. PHP is measurable at an early stage of larval development and can be erased over a matter of days. Interestingly, at high temperatures, PHP induced by impairing glutamate receptor function either fails or falls short of full compensation.

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This failure appears to correlate with impaired NMJ growth in the same animals. If PHP is a readily reversible homeostatic process, why is there a days-long time lag to reverse it? For the current study, this likely means that the temperature downshifts in the reversibility experiments represented an opportunity for the NMJ to incorporate endogenous WT GluRIIA into a significant number of new PSDs while it continued to grow.

This would restore electrophysiological parameters to normal levels, which is consistent with the data. Reversibility of rapid and sustained forms of homeostatic plasticity Yeates, The majority of recent studies about synaptic homeostasis at the Drosophila NMJ have emphasized that presynaptic adjustments to neurotransmitter release properties must occur within minutes of drug-induced PhTox postsynaptic receptor inhibition to induce a rapid and offsetting response to PhTox challenge.

For almost all of the cases in which a mutation or an experimental condition blocks the short-term induction of homeostatic signaling, the same perturbation has also been shown to block its long-term maintenance. Interestingly, however, the converse is not true. Additional studies have shown that the long-term consolidation or expression of homeostatic signaling at the NMJ can be genetically uncoupled from its induction. Select molecules seem to be dedicated to a long-term maintenance program that involves protein translation and signaling processes in both the neuron and the muscle.

Recent data suggest that such long-term processes may take 6 h or more to take full effect Yeates, As more molecular details about HSP are elucidated, it will be interesting to test whether the rapid induction and sustained consolidation of PHP can be reversed by similar or separate mechanisms, and what the time courses of those reversal mechanisms are. At the mouse NMJ, reversibility was recently demonstrated pharmacologically. Within seconds of drug application, QC increased—and then within seconds of drug washout, it decreased again Wang, b.

Follow-up experiments suggested that those rapid, dynamic changes in PHP dynamics at the mouse NMJ were mediated by a calcium-dependent increase in the size of the RRP of presynaptic vesicles Wang, b. It is instructive to consider mammalian synaptic preparations and study how homeostatic forms of synaptic plasticity are turned on and off. Groundbreaking work on cultured excitatory vertebrate synapses showed that in response to activity deprivation or promotion , synapses employ scaling mechanisms by adding or subtracting AMPA-type glutamate receptors to counteract the perturbation.

Bidirectional scaling suggested that reversible mechanisms likely dictate homeostatic scaling processes. Complementary studies testing scaling reversibility have borne out this prediction. Additionally, evidence for reversible forms of homeostatic scaling have been found in rodent sensory systems, such as auditory synapses after hearing deprivation and restoration to reverse and in the visual cortex after light deprivation. Collectively, the vertebrate and invertebrate studies support the notion that reversible fine-tuning is an efficient strategy used to stabilize activities in metazoan nervous systems.

One advantage offered by the Drosophila system is a genetic toolkit to uncover possible reversibility factors. Partial or failed homeostatic signaling at high temperatures Yeates, Are there environmental limitations for homeostatic potentiation at the Drosophila NMJ?

Clearly there are. Likewise, reduced glutamate receptor function alone does not appear to be a sufficient barrier to impair PHP. It is not clear what the molecular or anatomic basis of this limit on PHP is. The limitation seems to be on homeostatic signaling that supports PHP at high temperatures in the face of the dominant-negative transgene expression Yeates, Temperature effects on neurophysiology are well documented. Recent work in crustaceans demonstrates that robust and reliable circuits such as the neurons driving the rhythmicity stomatogastric nervous system can fail under extreme temperature challenges.

For the Drosophila NMJ, prior studies of larval development documented a significant enhancement of synaptic arborization when larvae were raised at higher temperatures. Additional studies have shown that NMJ growth plasticity can be additionally affected by mutations that affect neuronal excitability. Given the backdrop of these data, it is not unreasonable to hypothesize that the tolerable limits of synaptic activity challenge could be different at different temperatures Yeates, It must be noted that the data suggest that the coping capacity of the NMJ is dependent on genotype.

WT NMJs cope at all temperatures. Why do these differences persist? It is not clear. The answer could relate to the well-documented temperature-induced alterations in NMJ growth, or alternatively, a limited availability of synaptic factors that are needed to cope with a double challenge of high temperature and particular impairment of glutamate receptor function. Future molecular and physiologic work will be needed to unravel those possibilities in the contexts of different genetic backgrounds and culturing conditions Yeates, Distinct homeostatic modulations stabilize reduced postsynaptic receptivity in response to presynaptic DLK signaling Synapses are constructed with the stability to last a lifetime, yet sufficiently flexible to adapt during injury.

Although fundamental pathways that mediate intrinsic responses to neuronal injury have been defined, less is known about how synaptic partners adapt. This study investigated responses in the postsynaptic cell to presynaptic activation of the injury-related Dual Leucine Zipper Kinase pathway at the Drosophila neuromuscular junction.

The postsynaptic compartment reduces neurotransmitter receptor levels, thus depressing synaptic strength.

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Interestingly, this diminished state is stabilized through distinct modulations to two postsynaptic homeostatic signaling systems. First, a retrograde response normally triggered by reduced receptor levels is silenced, preventing a compensatory enhancement in presynaptic neurotransmitter release. However, when global presynaptic release is attenuated, a postsynaptic receptor scaling mechanism persists to adaptively stabilize this diminished neurotransmission state.

Thus, the homeostatic set point of synaptic strength is recalibrated to a reduced state as synapses acclimate to injury Goel, Neurons are endowed with robust surveillance systems that detect injury and initiate latent plasticity programs involving regenerative and degenerative responses. A fundamental signaling system induced after neuronal injury is mediated by an evolutionarily conserved mitogen-activated protein kinase called Dual Leucine Zipper Kinase DLK. DLK signaling initiates translational changes in axons and transcriptional responses in the nucleus that ultimately promotes degeneration at the distal axon and regeneration proximal to the site of injury.


At the Drosophila neuromuscular junction, highwire hiw encodes an E3 ubiquitin ligase that constitutively degrades the DLK homolog Wallenda Wnd. However, after axonal injury, Wnd is no longer degraded by Hiw, leading to increased Wnd protein levels and activation of regenerative and degenerative signaling programs. Genetic loss of hiw in neurons constitutively activates Wnd signaling, while neuronal overexpression of wnd can overcome Hiw-mediated degradation to activate this same program. This relationship between PHR proteins, DLK activity, and injury-related signaling is conserved in other invertebrate and mammalian systems.

Thus, loss of hiw or overexpression of wnd f in neurons activates an intrinsic signaling system that transforms the cell into a state of persistent degenerative and regenerative adaptations related to a programmed response to injury Goel, For example, foundational studies at the mouse NMJ have demonstrated that motor neuron injury, denervation, or synapse elimination can provoke disassembly and remodeling of the postsynaptic specialization, including a diminution of neurotransmitter receptor levels, which can precede obvious changes in the overlying nerve terminal.

There is also evidence for neuronal and synaptic remodeling in the spinal cord and other areas in the central nervous system following injury. At the glutamatergic Drosophila NMJ, an apparent reduction in the synaptic response to glutamate quantal size was shown in hiw mutants as well as following a 'nerve crush' injury to otherwise wild-type NMJs. At the Drosophila NMJ, two forms of homeostatic plasticity have been described that stabilize synaptic strength in response to perturbations that would otherwise disrupt functionality.

First, pharmacological or genetic manipulations that diminish postsynaptic glutamate receptor GluR function initiate a retrograde signaling system. Specifically, a retrograde signal emitted from the muscle instructs the neuron to compensate by increasing presynaptic glutamate release to restore set point levels of synaptic strength.

This process is conserved in rodents and humans, and is termed presynaptic homeostatic potentiation PHP because the expression mechanism of this form of plasticity is a presynaptic increase in neurotransmitter release. Second, hypo-innervation of the NMJ induces a distinct form of adaptive plasticity.

In this situation, a reduction in presynaptic neurotransmitter release is observed proportional to the reduction in synapse number. In response, a homeostatic increase in quantal size is induced that stabilizes synaptic strength. However, to what extent these homeostatic mechanisms operate at synapses that have adapted to injury-related signaling is unknown Goel, This study has characterized synaptic structure, function, and plasticity at NMJs with active Wnd signaling in presynaptic neurons, with a particular focus on how the postsynaptic muscle responds.

This analysis has revealed that the postsynaptic muscle responds by diminishing GluR abundance and by silencing the retrograde homeostatic signaling system that would normally enhance presynaptic release following reduced GluR levels. However, this subdued state of synaptic strength is homeostatically maintained through adaptive modulations to postsynaptic GluR levels following hypo-innervation. Together, this illuminates the distinct signaling systems targeted for modulation in the postsynaptic cell that stabilize a muted synaptic state in response to presynaptic Wnd signaling Goel, Although there are clearly myriad changes induced in neurons following Wnd activity, at the Drosophila NMJ, no evidence was found for hiw or wnd having any functions in the postsynaptic muscle.

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Although Wnd has no apparent function in regulating presynaptic neurotransmitter release, its negative regulator, Hiw, does have an independent function in promoting neurotransmitter release. The putative substrate that mediates this role for Hiw is unknown, but must be separate from Wnd and the downstream pathways orchestrated through Wnd signaling. Therefore, following injury, inhibition of Hiw exerts two separate influences that mutes functionality at both synaptic compartments: First, Wnd is activated to provoke a diminished state of responsiveness in the muscle, and second, presynaptic neurotransmitter release is reduced.

The substrate that mediates the Wnd-independent role of Hiw to reduce presynaptic efficacy is unknown, but will be an interesting target to define in future studies Goel, It is remarkable that although Wnd signaling is driven solely in the presynaptic compartment at the NMJ, this process is sensed and transforms the postsynaptic muscle into a novel state characterized by subdued responsiveness to presynaptic activity.

Neuronal Wnd signaling must therefore impart anterograde information to the muscle. Importantly, this information is communicated independently of altered synaptic development and structure, as well as evoked neurotransmission. An attractive possibility is that trans-synaptic adhesion proteins may mediate the activity-independent anterograde signaling following presynaptic Wnd activation. Indeed, multiple extracellular cues and trans-synaptic signals interpose a rich dialog between presynaptic terminals, postsynaptic compartments, and the extracellular matrix at synapses.

Trans-synaptic 'nanocolumns' have recently emerged as inter-cellular signaling complexes that orchestrate synaptic remodeling and plasticity in addition to development, maturation, and structural alignment at synapses. It is tempting to speculate that direct interactions through these nanocolumns may communicate injury-related signaling from presynaptic terminals to postsynaptic partners to remodel receptor fields and plasticity pathways.

One major outcome of the response in muscle to presynaptic Wnd signaling is a diminution of postsynaptic neurotransmitter receptors. This parallels observations at the mouse NMJ following denervation or synapse elimination, in which a reduction in neurotransmitter receptor levels and protein synthesis in muscle has been demonstrated. This selective loss-of-acetylcholine receptors at synaptic sites is a result of removal of receptors from these areas coupled with a lack of insertion of new receptors.

In addition, the decreased synaptic protein levels observed in the muscle following neuronal Wnd signaling may be result from modulation of Tor activity, as postsynaptic overexpression of Tor globally elevates protein synthesis and partially restores receptor levels. Finally, an intriguing study in the rodent visual system revealed that ablation of presynaptic photoreceptors leads to remodeling of the postsynaptic apparatus, including the rapid and localized disappearance of GluRs.

Together, these studies demonstrate that postsynaptic targets adapt to injury, disease, and loss-of-presynaptic inputs by remodeling postsynaptic neurotransmitter receptor complexes to reduce sensitivity, suggesting a conserved response Goel, While beneficial effects of fasting on organismal function and health are well appreciated, little is known about the molecular details of how fasting influences synaptic function and plasticity. Genetic and electrophysiological experiments demonstrate that acute fasting blocks retrograde synaptic enhancement that is normally triggered as a result of reduction in postsynaptic receptor function at the Drosophila larval neuromuscular junction NMJ.

This negative regulation critically depends on transcriptional enhancement of eukaryotic initiation factor 4E binding protein 4E-BP under the control of the transcription factor Forkhead box O Foxo. Furthermore, the findings indicate that postsynaptic 4E-BP exerts a constitutive negative input, which is counteracted by a positive regulatory input from the Target of Rapamycin TOR. This combinatorial retrograde signaling plays a key role in regulating synaptic strength.

These results provide a mechanistic insight into how cellular stress and nutritional scarcity could acutely influence synaptic homeostasis and functional stability in neural circuits Goel, One mechanism that stabilizes the reduced state of synaptic strength following neuronal Wnd signaling is a selective occlusion of postsynaptic PHP transduction. Neurons experiencing Wnd signaling are competent to homeostatically modulate presynaptic neurotransmitter release, but apparently do not receive the retrograde information necessary from the muscle, even following additional perturbations to or restorations of postsynaptic GluRs.

Interestingly, perturbations to Cap-dependent protein synthesis in the postsynaptic muscle have been shown to disrupt PHP retrograde signaling, and metabolic changes in the muscle can also impinge on this pathway to modulate PHP signaling Kauwe, This indicates that one mechanism utilized by the muscle to respond to neuronal Wnd signaling, distinct from a general reduction in protein synthesis, may be a selective inhibition of Tor-dependent protein synthesis which, in turn, contributes to the occlusion of PHP signaling.

It is interesting to note that while PHP signaling is highly compartmentalized, it can be still be expressed in neurons despite perturbations to a variety of processes that disrupt synaptic structure and function independently of injury-related signaling. Thus, an instructive cue mediated by Wnd signaling selectively impairs retrograde PHP communication in the muscle to stabilize a reduced level of synaptic strength Goel, Although PHP signaling appears to be inhibited, a second mechanism stabilizes the reduced set point of synaptic strength following neuronal Wnd signaling, GluR scaling.

This postsynaptic form of homeostatic plasticity parallels the postsynaptic scaling of GluRs observed following silencing of neuronal activity in mammalian central synapses. At the Drosophila NMJ, the induction of this form of homeostatic plasticity was known to require hypo-innervation, and this study has shown that a selective increase in postsynaptic GluRIIA-containing receptors compensates for reduced neurotransmitter release and maintains stable synaptic strength.

Although the signal transduction system that mediates this form of plasticity is enigmatic, it is clearly distinct from the retrograde signaling system that drives PHP. The homeostatic set point of synaptic strength has been demonstrated to be plastic, and can be stabilized at levels distinct from baseline values in mutations that disrupt synaptic function and during aging of the synapse.

The current results define injury-related signaling as an additional process that has the capacity to adjust the homeostatic set point of synaptic strength Goel, Why might synaptic strength be adjusted to a reduced level following injury? The coordinated reduction in Wnd-mediated postsynaptic responsiveness and Hiw-mediated presynaptic efficacy may promote sufficient time for the process of repair vs.

Loss or further reductions to neurotransmission may destabilize synaptic integrity, impairing the series of subsequent steps necessary to restore normal synaptic strength and structure should the injury be successfully overcome. In addition, a further reduction in postsynaptic receptivity may deprive the neuron of necessary trophic support and promote neuronal degeneration.

Indeed, a lack of trophic support from the muscle due to weakened synaptic activity contributes to neuromuscular disease pathogenesis. In the central nervous system, there is evidence that synaptically coupled cells sense and respond to injury. Hence, injury to an individual neuron can propagate and destabilize an entire neural circuit without adaptive counter measures.

The current findings illustrate the acclimations that occur in postsynaptic targets to neurons experiencing injury-related signaling and highlight the adaptations to synaptic plasticity that maintain stable functionality around a reduced set point of synaptic strength Goel, Collectively, these findings reveal the mechanism by which extracellular signalling can induce rapid cellular responses through regulation of the epitranscriptome.

They do not degrade but cleave substrates at limited sites. Calpains are implicated in various pathologies, such as ischemia, injuries, muscular dystrophy, and neurodegeneration. Despite so, the physiological function of calpains remains to be clearly defined. Calpains enrich at the postsynaptic area, and the calcium-dependent activation of calpains induced cleavage of GluRIIA at Q of its C terminus.

Further genetic and biochemical experiments revealed that different calpains genetically and physically interact to form a protein complex. These data provide a novel insight into the mechanisms by which different calpains act together as a complex to specifically control GluRIIA levels and consequently synaptic function Metwally, Calpains are a family of calcium-activated cytoplasmic cysteine proteases, which are ubiquitously expressed in various mammalian tissues and are functionally active at neutral pH.

Members of the calpain family act in pathological processes associated with calcium overload, such as ischemia and Alzheimer's disease. For example, calpains cleave multiple synaptic proteins, including both inotropic and metabotropic glutamate receptors in excitotoxic conditions, as well as in synaptic plasticity Chan, ; Xu, ; Doshi, ; Baudry, However, little is known of the precise physiological function of calpain-dependent cleavage of target proteins at synapses during normal development Metwally, Calpains exist in organisms ranging from bacteria to humans.

To date, 15 different calpains have been identified in mammals and four in Drosophila. Unlike most proteases, calpains do not destroy but cleave their substrates at limited sites to modulate their function. They are activated in vitro by micromolar and millimolar concentrations of calcium, respectively. Conventional calpains 1 and 2 are heterodimers composed of a large catalytic subunit with four domains dI-dIV and a small regulatory subunit with two domains dV and dVI. Heterodimerization of the large and small subunits occurs through a unique interaction between their C-terminal domains.

These sites, together with domains IV and VI, interact with calcium and are required for full enzymatic activity. Calpastatin is an endogenous calpain inhibitor that binds and inhibits calpains via its calpain-inhibitor domains when the proteases are activated by calcium Hanna, Unlike mammalian calpains, Drosophila calpains comprise a large subunit only and calpastatin has not been identified in Drosophila Metwally, The efficiency of neurotransmission is determined by the level of neurotransmitter receptors at the postsynaptic densities PSDs. However, the molecular mechanism by which the level of neurotransmitter receptors at synapses is regulated is not well understood.

As calcium is a highly versatile intracellular signal that regulates many different cellular functions, the finding of calpain proteinases activated by calcium under physiological conditions at NMJ synapses offers novel insights into the myriad of calcium-mediated processes at other cellular contexts Metwally, Neurotransmission efficiency is determined by the level of neurotransmitter receptors at the PSDs.

Therefore, the regulation of glutamate receptors at synapses has been under intensive studies. However, the molecular mechanism responsible for regulating the expression of neurotransmitter receptors at synapses is still poorly understood. Using genetic screening, together with optogenetic manipulation and calcium treatment, this study has revealed that GluRIIA protein levels were specifically and negatively regulated by calcium-dependent calpains during development Metwally, Extensive studies have demonstrated robust homeostatic regulation at the Drosophila NMJ.

Genetic or pharmacological manipulations that impair the protein level or activity of postsynaptic GluRs cause a compensatory increase in presynaptic action potential-evoked neurotransmitter release; the increase in evoked release precisely compensates for the decrease in GluR sensitivity and, thereby, maintains a normal level of transmission. This latter case is consistent with the finding that a high threefold increase of GluRIIA level in calpains mutant did not lead to upregulation of EJP amplitude.

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It is possible that the increase in mEJP amplitude is compensated by a downregulation of quantal content to maintain normal EJP amplitude in calpain mutants. However, this is not what we observed. Instead, we observed that GluRIIB was normally localized and its levels were unchanged when GluRIIA was upregulated, resulting from calpain mutation or knockdown, suggesting a distinct regulation of subunit composition by calpains at the NMJ Metwally, However, relatively little is known about the regulation of receptor movement within the cell membrane upon ligand binding.

This effect was prevented by the addition of the TRH receptor antagonist midazolam. Conclusion: These results demonstrate for the first time that not only agonist binding but also abundance of some signaling proteins may strongly affect TRH receptor dynamics in the plasma membrane.

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The authors would like to thank Dr. Jan Krusek for his assistance with calcium imaging experiments. No potential conflict of interest was reported by the authors. Skip to Main Content. Search in: This Journal Anywhere. Advanced search. In contrast, however, point-mutation of Tyr in the long PRLR isoform has only a partial effect on PRLR function , whereas the absence of this residue in bovine and cervine tissues that naturally lack this C-terminal tyrosine compared with other species is not detrimental to receptor activity , , indicating that alternative intracellular tyrosines can be used.

For example, a recent study has suggested an important role of Tyr in the transcriptional activation of the IRF-1 promoter , most probably through Stat1 activation see below. Why is receptor tyrosine phosphorylation required? Although available data remain limited, it appears that PRLR-mediated cell proliferation does not necessarily require tyrosine phosphorylation of the receptor. For example, a mutant form of the long PRLR truncated after 94 cytoplasmic residues G maintains the ability to activate Stats 1, 3, and 5 and to transduce a significant proliferative signal in murine 32D cells, presumably through signaling pathways involving these Stat molecules see below Although the phosphorylation status of this G mutant was not established by the authors , a mutational study of tyrosines in the intermediate PRLR suggests that this G mutant is not phosphorylated, although phosphorylation of tyrosine cannot be totally discarded Such discrepancies might reflect some differences inherent to the cell types e.

It thus appears premature to deduce any general rule with respect to PRLR domains required for proliferation. Since tissues expressing the PRLR presumably express more than a single isoform, this observation might be of considerable functional significance and represents an open area of investigation.

Activation of the IRF-1 promoter, a growth-related PRLR-target gene , , depends on both tyrosines and of the intermediate PRLR, and it has been suggested that these tyrosines, when phosphorylated, may serve as docking sites for recruiting Stat1 , However, we have shown that a mutant form of the long PRLR deleted of all its cytoplasmic tyrosines maintains the ability to transmit a weak lactogenic signal in the particular context of JAK2 overexpression, suggesting that the kinase can partially initiate PRLR signaling pathways In agreement, it has been suggested that JAKs by themselves are capable of generating a signal and activating promoters in the absence of a specific ligand-receptor interaction, correlating the ability of the kinase to phosphorylate Stat5 in vitro In conclusion, although current data do not unambiguously establish receptor phosphotyrosines as an absolute requirement for the activation of PRLR target genes, they undoubtedly enhance the signal of PRL on these genes.

Stats contain five conserved features: a DNA-binding domain, a SH3-like domain, a SH2 domain, a ubiquitous tyrosine and a C-terminal transactivating domain from the N- to C-terminus, respectively. A consensus model of Stat activation has been proposed on the basis of data collected from studies of the different cytokine receptors for additional information, see previously published reviews on Stat proteins, Refs. First, the cytokine-bound receptor undergoes tyrosine phosphorylation by the associated Janus kinase. Second, the phosphorylated tyrosine interacts with the SH2 domain of a Stat, making the latter a part of the receptor-JAK complex.

Third, the receptor-bound Stat is phosphorylated by the Janus kinases belonging to the complex. Fourth, the phosphorylated Stat dissociates from the receptor, homo- or heterodimerizes through an interaction involving the phosphotyrosine of each monomer and the SH2 domain of the other Stat molecule, and finally the dimer translocates to the nucleus where it activates specific DNA elements found in the promoters of cytokine target genes. The specificity of a cytokine receptor is believed to be driven, at least in part, by the number and type of Stat proteins it can activate.

In , the transcription factor named MGF mammary gland factor was identified from sheep mammary gland and, in view of the high structural similarity with the other Stat proteins known at that time, it was further renamed Stat5 , All isoforms possess the functionally essential tyrosine , identified by Gouilleux and collaborators as the tyrosine being phosphorylated by JAK2. Similarly, when the C-terminal domain of Stat5 is truncated which removes the tyrosine phosphorylation site , such mutants function as a dominant-negative — Finally, it is noteworthy that in the specific context of cytokine chimeric receptors, JAK1 and possibly JAK3 can also phosphorylate Stat5 on tyrosine In agreement with the consensus model of Stat recruitment by receptor phosphotyrosines, we have shown that in the long PRLR, tyrosines , , and which are all phosphorylated in the context of single-tyrosine mutants , are sufficient to activate Stat5, although Tyr is clearly the most potent in this respect In contrast, others have reported that a C-terminal truncated form of the long PRLR G, lacking Tyr is able to stimulate Stat5 tyrosine phosphorylation , although the transcriptional activity of this mutant on a PRL-responsive reporter gene was not assessed.

Although these apparent discrepancies might reflect species specificity of cellular systems used for bioassays, or of PRLR , they might also indicate that Stat5 tyrosine phosphorylation is required , but not necessarily sufficient for activation of transcriptional activity. In human, mouse, and rat Stat5a, but not Stat5b, a very similar tetrapeptide is found at the homologous position R -L-S-P. Although this sequence does not perfectly match the MAP kinase consensus site, it might be a target for another proline-directed kinase In this respect, heterodimerization of Stat5a and Stat5b has been recently reported by several investigators — Moreover, Kirken et al.

Whether this observation reflects any functional difference between these two closely related transcription factors awaits further investigation. Finally, Yu-Lee and colleagues , , have shown recently that Stat5a and Stat5b exert an inhibitory effect on PRL-inducible IRF-1 promoter activity, and these authors have proposed this inhibition to involve squelching by Stat5 of a factor that Stat1 requires to stimulate the IRF-1 promoter. The region s of the PRLR required for activation of these Stats remain poorly documented, although the 93 membrane-proximal residues have been reported to be sufficient for tyrosine phosphorylation of both Stats 1 and 3 In the context of the GHR, it has recently been hypothesized that phosphotyrosine s of JAK2 could also bind to Stat3, in agreement with the presence of the consensus Stat3-binding site see below in the kinase , , , Although such an interaction does not preclude the possible occurrence of interactions also with the receptor, this hypothesis remains to be tested in the context of Stat activation by the PRLR.

As described above, within a given receptor cytoplasmic domain, not all tyrosines undergo phosphorylation upon ligand-mediated receptor activation. The molecular features directing one tyrosine, and not another, to become phosphorylated are still poorly understood. Obviously, one requirement is the accessibility of the residue by the kinase.

A phosphotyrosine must be recognized by at least three types of signaling proteins: the tyrosine kinase, the tyrosine phosphatase that will down-regulate the signal, and the SH2- or any other motif recognizing phosphotyrosine containing protein s that will dock on the phosphotyrosine. It is usually accepted that some of these interactions are driven by the recognition of specific sequences surrounding the phosphotyrosine , Attempts have thus been made to correlate the ability of cytokine receptors to bind a given subset of Stat proteins with the presence of consensus sequences in the near environment of their cytoplasmic phosphotyrosines , — Regarding Stat5 recruitment by the long PRLR, no sequence similarity could be found around the three phosphorylated tyrosines involved Tyr , Tyr , Tyr ; see above and Fig.

In contrast, the three other phosphotyrosines, which do not lead to Stat 5 activation, i. In fact, the sequence bordering Tyr is more closely related to that described for insulin receptor substrate-1 IRS-1 binding. Consensus DNA motifs specifically recognized by Stat complexes have been identified in the promoters of target genes. The specificity of the interaction between a particular Stat and a GAS motif found in a given target promoter has been proposed to depend, at least in part, on the center core nucleotide s The activation of identical Stat proteins by different cytokine receptors questions the mechanisms by which specificity of signaling pathways is achieved in response to a particular hormonal stimulation.

For example, it has recently been reported that Stat5 interacts with the glucocorticoid receptor This functional cooperation seems to require specific DNA binding of Stat5, but not of the glucocorticoid receptor A , although this hypothesis remains controversial Although the JAK-Stat cascade is presumably the most important signaling pathway used by cytokine receptors, other transducing pathways are also likely involved in signal transduction by these receptors. Activation of the MAPK pathway has been reported in different cellular systems under PRL stimulation , , — , , , Activation of the nucleotide exchange protein Vav has also been reported Although the JAK-Stat and the MAPK cascades were initially regarded as independent pathways, several recent data suggest rather that they are interconnected Association of the PRLR with Src, the prototype member of this kinase family, has also been reported after PRL stimulation in lactating rat hepatocytes The role of Src kinases in signal transduction by PRLRs remains unknown, although promotion of cell growth has been suggested Accordingly, several recent studies pointed out a role of tyrosine phosphatases in PRLR signaling , , , although the mechanism by which they are regulated, as well as their substrates, remain poorly documented.

Finally, PRL has been shown to increase the concentration of intracellular calcium in PRLR-transfected CHO cells, although the physiological meaning of this phenomenon remains to be elucidated The same group proposed the involvement of these guanine nucleotide- binding proteins in the mitogenic action of PRL on Nb2 cells A potentially new signal transducer has been recently identified in rat ovary and appears to be specific to this tissue Almost all of the effects attributed to PRL in vertebrates 92 , are the subject of conflicting observations and despite an amazing accumulation of articles, the precise role of lactogenic hormones, with the clear exception of direct mammary effects, remains an open question.

Lactogens thus remain well characterized hormones with multiple but, in many cases, not well characterized functions. In vivo , two animal models have been developed to study PRL action: one utilizes lowering PRL levels, achieved either by hypophysectomy or administration of dopamine D 2 receptor agonists; the second is based on the use of spontaneous mutant dwarf mice strains, lacking pituitary somatotrophs and lactotrophs.

D , and by the unavoidable suppression of other pituitary and nonpituitary hormones. In vitro models suffer similar limitations. FCS, an essential component of most cell and tissue culture media, contains high concentrations of lactogenic hormones that are difficult to remove In addition, a growing list of cells see Section II. By the technique of gene targeting in mice , we have produced the first experimental model in which the effects of a complete absence of PRLR-mediated signaling of lactogenic hormones can be observed Cell lines derived from this particular mouse offer the potential of in vitro models to further explore the indirect and direct effects of PRL.

The vast majority of mutations created by homologous recombination in embryonic stem cells to date have been null alleles. The next level of sophistication requires that a gene be inactivated or modified in specific tissues or at a certain time during the life of the animal conditional knockouts or knockins. B ; see Refs. The short and long forms are differentially expressed or regulated during the estrous cycle and pregnancy 52 , , , which suggests that they may initiate distinct signaling pathways.

Loss of just one cysteine of exons 4 or 5 encoding extracellular subdomain D1 results in complete lack of hormone-binding activity A targeting construct was prepared with 7. After electroporation into E F1 intercrosses revealed a genotype distribution not significantly different from the normal Mendelian ratios excluding the first generation By Northern blotting, a single major mRNA transcript of 2. The PRLR protein was immunoprecipitated from solubilized liver microsomes and analyzed by immunoblot.

Histological examination of the mammary glands showed that lactational performance was correlated with the degree of mammary gland development Fig. These results demonstrate that two functional alleles of the PRLR are required for efficient lactation and that this phenotype in heterozygotes is primarily due to a deficit in the degree of mammary gland development. Alveoli are indicated by white arrows , while ducts are indicated by black arrows. Note engorged alveoli. Note absence of alveoli and dominant ductal tissue.

The mammary gland undergoes development in utero , at puberty mainly ductal development , and during pregnancy ductal and alveolar development. These hormones produce some development with each estrous cycle and massive development at pregnancy, which never fully regresses after estrus or weaning, resulting in ever increasing alveolar and ductal development with each episode Our observations suggest that the epithelial cell proliferation during pregnancy and the postpartum period depends on a threshold of PRLR expression which is not achieved with just one functional gene, given that the level of PRLR is closely controlled in mammary gland In heterozygous mice where the level of the receptor is reduced, mammary gland proliferation is insufficient to ensure lactation at the first pregnancy but further estrous cycles or a single pregnancy lead to the development of a mammary gland capable of producing milk.

When the mother reformed the nest, a pup was often left outside and not retrieved, while the others were suckled. Other processes regulated by the hypothalamus, such as eating, sexual behavior, and locomotor activity, appear to be normal in PRLR mutant mice. This was confirmed by examination of estrogen levels which showed a marked increase on day 3 after the vaginal plug, as the animals again entered estrus. The irregular mating patterns of the females indicate an alteration of estrous cyclicity. Multiple abnormalities were observed: fewer eggs were fertilized, oocytes at the germinal vesicle stage were released from the ovary, and fragmented embryos were found.

Single cell-fertilized eggs were recovered, suggesting for most oocytes that an arrest of development occurred immediately after fertilization. On the left, normal egg development is represented. Undeveloped oocytes are depicted in white including oocytes at the germinal vesicle stage, oocytes that have expulsed the first polar body, and degenerated embryos , and 1 cell and 2 cell embryos, morula and blastocysts are color-coded. Most of the fertilized eggs produced normal embryos.

Thus, the absence of PRLR in female mice results in reduced ovulation, reduced fertilization, and almost complete arrest of preimplantation development. The outcome is complete sterility. Most of these were found on days 2. A higher level of PRL is seen in follicles containing mature oocytes capable of being fertilized , — , although others found no relationship or suggest a negative effect PRL was found to increase the rate of germinal vesicle breakdown and subsequent fertilization and correct development in vitro Fertilization rates were reduced, indicating that this effect is a result of a maternal deficiency.

This may involve incomplete oocyte maturation, or a defect in the oviduct such as a reduced sperm transport to the ampulla or loss of a factor that enhances fertilization. Divergent effects of PRL on the rate of implantation development of mouse embryos have been reported — The present studies exclude the absolute requirement for an oocyte PRLR in pre- and postimplantation embryonic development, supporting previous investigations , and indicating that the defect must reside in the environment in which the embryo develops.

A number of factors in the oviduct that influence preimplantation development may be affected by the PRLR mutation. Estrogen and progesterone can influence the rate of ovum transport and preimplantation development The failure of trophic support of the corpus luteum by PRL would be expected to reduce progesterone levels on day 2. Candidates include ovum factor, now identified as platelet activating factor PAF , released by the fertilized eggs , and early pregnancy factor EPF , a multifactorial activity comprised of PAF, thirodoxin , chaperonin 10 , and other uncharacterized molecules produced by the platelets of the oviduct and ovary in response to embryonic PAF EPF is present in serum 24 h after ovulation and stimulates lymphocytes to produce a suppressor of the delayed-type hypersensitivity reaction, potentially protecting the ovum from the maternal immune system and promoting embryo cleavage, in addition to acting as a growth factor Uterine preparation for embryo implantation is dependent upon continued estrogen and progesterone secretion by the corpus luteum of the ovary, which is supported by the pituitary in rodents during the first half of pregnancy PRL has been shown to stimulate progesterone synthesis by dispersed ovarian cells from midpregnant mice , demonstrating that lactogenic hormones can directly stimulate ovarian progesterone secretion.

Furthermore a nidatory ovarian estrogen surge is required to allow embryo implantation Recently, multiple reproductive failures similar to those observed in PRLR knockout mice have been reported in cyclooxygenase 2-deficient mice A. Testes and accessory organs were of normal size; their histological examination showed no obvious morphological or histological abnormalities: clearly defined germinal cell layers and spermatocytes were present in the seminiferous tubules. PRL may regulate testosterone production by Leydig cells via modulation of the effects of LH and of the level of its receptor PRL has been also proposed to be involved in sperm capacitation : a short period of incubation with PRL has been reported to enhance in vitro fertilization rates , while longer periods reduce in vitro fertilization rates , , although others have seen no effect PRL can also influence the function of the accessory reproductive glands , Although no effect on the mammary gland of heterozygous animals has been reported for null mutations of the progesterone receptor gene , the complete absence of this receptor in homozygous animals results in a gland lacking terminal-end buds with some branched ducts Although estradiol receptor knockout females are infertile, to our knowledge, no particular mammary gland phenotype has been reported In Stat5a-deficient mice, mammary lobuloalveolar outgrowth during pregnancy was curtailed, and females were unable to lactate after parturition because of a failure of terminal differentiation Similar phenotypes have been recently reported in PRL knockout mice Interestingly, Stat5b, but not Stat5a-deficient females exhibit severely compromised fertility.

Moreover, the phenotype of Stat5b knockout mice is distinct from that of Stat5a-deficient mice by a decrease in body growth profile in the former. Mice homozygous for a germline mutation in A- myb , a nuclear protein regulator of transcription, show a marked underdevelopment of the breast epithelial compartment after pregnancy.

Consequently, mice are unable to nurse their newborn pups, demonstrating a critical role of A- myb in mammary gland development Mice lacking the cyclin D1 gene also exhibit a dramatic impairment of mammary gland development leading to inability to lactate their litters In view of the putative immunomodulatory role of PRL, we are currently analyzing the immune phenotype of the knockout animals.

Preliminary data suggest that maturation and export of precursor cells occur in the thymus and, to date, no abnormality in the export of the lymphoid system to the periphery has been identified. Interestingly, no immune phenotype was seen in mice lacking the PRL gene The level of the mRNA encoding the long form of PRLR in osteoblasts is comparable to that observed in other cells such as thymocytes, mammary cells, or bone marrow cells. No expression of any form was found in osteoclast-like cells.

PRLR expression rises dramatically in a number of rodent tissues during the late stages of pregnancy, and PRL and PLs are detectable in fetal blood , , suggesting that lactogenic hormones begin to exert major effects during this period in preparation for the transfer to autonomous life. A number of phenotypes were observed in both hetero- and homozygous animals see Table 8.

It is probable that most of the phenotypes observed are related to the absence of the long form of the receptor, since this is the major isoform in all cells involved in reproductive function. Almost every aspect of female reproduction is altered in these animals, unambiguously demonstrating that the PRLR is a key regulator of reproduction. The ability of this new model to provide novel insights into the function of lactogenic hormones and their receptor illustrates the power of the knockout approach to discover and confirm specific roles for well investigated molecules.

The generation of knockouts has highlighted the role of many genes in embryonic development, yet the study of phenotypes associated with null alleles is only an initial step in the analysis of the gene function. We can look forward, in the near future, to the widespread application of approaches of greater technical sophistication, including the generation of subtle alterations in the gene sequence and conditional knockouts.

PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body.

In agreement with this wide distribution of receptors is the fact that now more than separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function.

A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone.

The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor.

Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic Stat proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. The technique of gene targeting in mice has been used to develop the first experimental model in which the effects of the complete absence of any lactogen or PRL-mediated effects can be studied.

Twenty per cent of the homozygous males showed delayed fertility. Other phenotypes, including effects on the immune system and bone, are currently being examined. It is clear that there are multiple actions associated with PRL. The fact that extrapituitary PRL can, under some circumstances, compensate for pituitary PRL raises the interesting possibility that there may be effects of PRL other than those originally observed in hypophysectomized rats. The PRLR knockout mouse model should be an interesting system by which to look for effects activated only by PRL or other lactogenic hormones.

On the other hand, many of the effects reported in this review may be shared with other hormones, cytokines, or growth factors and thus will be more difficult to study. Although PRL evolved several hundred million years ago, we are now at the end of the 20th century just beginning to understand how the hormone acts and its potential involvement in pathological disease states. Future research will center on further expanding the already long list of PRL actions and attempt to better understand the mechanisms of action of this intriguing hormone.

We thank Drs. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Distribution of the PRLRs. Biological Functions of PRL. Summary and Conclusions. Oxford Academic. Google Scholar. Vincent Goffin. Marc Edery. Nadine Binart. Paul A. Address reprint requests to: Paul A. Cite Citation. Permissions Icon Permissions. Introduction II. PRL A. PRL gene and primary structure C.

PRL tertiary structure D. The class 1 cytokine receptor superfamily B. PRLR gene and primary structure C. PRLR tertiary structure D. Water and electrolyte balance B. Growth and development C.

Receptors: Signal Transduction and Phosphorylation Cascade

Endocrinology and metabolism D. Brain and behavior E. Reproduction F. Immunoregulation and protection G. Actions associated with pathological disease states VI. Other signaling pathways VII. Impaired mammary gland development and lactation in heterozygous females D. Heterozygote maternal behavior E. Homozygous females are sterile F. Homozygous male fertility G. Other gene-targeted mutations leading to impaired mammary gland and reproductive function H.

Summary and Conclusions I. Introduction PRL and GH, along with placental lactogens PLs , form a family of hormones that probably result from the duplication of an ancestral gene. PRL tertiary structure Secondary structure studies circular dichroism, etc. Figure 1. Open in new tab Download slide. Figure 2. Table 1. Open in new tab. Table 2. Table 3. Table 4. Table 5. Table 6. Table 7. Figure 3. Figure 4. Figure 5.

Table 8. The preparation, identification and assay of prolactin - a hormone of the anterior pituitary. Search ADS. Structural features of prolactins and growth hormones that can be related to their biological properties. Sequences of pituitary and placental lactogenic and growth hormones: evolution from a primordial peptide by gene duplication.

Sequence-function relationships within the expanding family of prolactin, growth hormone, placental lactogen and related proteins in mammals. Cloning of bovine prolactin cDNA and evolutionary implications of its sequence. Tilapia prolactin: molecular cloning of two cDNAs and expression in Escherichia coli. Structural variants of prolactin: occurrence and physiological significance. Raven Press, New York, pp. Elsevier Science Publishers, Amsterdam, pp. The human placental lactogen genes: structure, function, evolution and transcriptional regulation. Circular dichroism studies on human pituitary growth hormone and ovine pituitary lactogenic hormone.

Three-dimensional structure of a genetically engineered variant of porcine growth hormone. De Vos. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects.

Studies of insulin, growth hormone and prolactin binding: tissue distribution, species variation and characterization.