Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.

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Prolactin: Structure, Function, and Regulation of Secretion

Publisher Summary Turns are a fundamental class of polypeptide structure and are defined as sites where the peptide chain reverses its overall direction. In the past 20 years, the peptide field has witnessed major development, stimulated by the discovery of a host of bioactive peptides. Turn structures have been proposed and implicated in the bioactivity of several of these naturally occurring peptides. In addition, many structural details of turns have been derived from conformational studies of model peptides. During this same period, more than 100 complete protein structures have been elucidated in single-crystal X-ray studies. These examples document the rich diversity of structural patterns in the chain folds of native proteins. Turns are intrinsically polar structures with backbone groups that pack together closely and side chains that project outward. Such an array of atoms may constitute a site for molecular recognition, and indeed, the literature abounds with suggestions that turns serve as loci for receptor binding, antibody recognition, and post-translational modification. In peptides, turns are the conformations of choice for simultaneously optimizing both backbone–chain compactness (intramolecular nonbonded contacts) and side-chain clustering (to facilitate intermolecular recognition). Presence of turns in bioactive conformations may in fact also reflect the lack of alternative conformational possibilities. The aim of this chapter is to examine structural and functional roles of turns in peptides and proteins.

Turns in peptides and proteins.

The endogenous morphinomimetic brain peptides Met5-enkephalin and alpha-, beta-, and gamma-endorphins have been evaluated in rats after intracerebrospinal fluid injection. beta-Endorphin produces marked, prolonged muscular rigidity and immobility similar to a catatonic state, counteracted by the opiate antagonist naloxone; this effect occurs at molar doses 1/100 to 1/400 that at which the other peptides or morphine block the response to painful stimuli. All peptides evoked dose-related, naloxone-reversible, wet-dog shakes in rats that had not been exposed to drugs. beta-Endorphin produced hypothermia, whereas gamma-endorphin produced hyperthermia. Such potent and divergent responses to naturally occurring subtances suggest that alterations in their homeostatic regulation could have etiological significance in mental illness.

https://science.sciencemag.org/content/sci/194/4265/630.full.pdf

Endorphins: profound behavioral effects in rats suggest new etiological factors in mental illness.

The distribution of immunoreactive enkephalin in rat brain and spinal cord was studied by immunoperoxidase staining using antiserum to leucine-enkephalin ([Leu5]-enkephalin) or methionine-enkephalin ([Met5]-enkephalin). Immunoreactive staining for both enkephalins was similarly observed in nerve fibers, terminals and cell bodies in many regions of the central nervous system. Staining of perikarya was detected in hypophysectomized rats or colchicine pretretated rats. The regions of localization for enkephalin fibers and terminals include in the forebrain: lateral septum, central nucleus of the amygdala, area CA2 of the hippocampus, certain regions of the cortex, corpus striatum, bed nucleus of the stria terminalis, hypothalamus including median eminence, thalamus and subthalamus; in the midbrain: nucleus interpeduncularis, periaqueductal gray and reticular formation; in the hind brain: nucleus parabrachialis, locus ceruleus, nuclei raphes, nucleus cochlearis, nuclear tractus solitarii, nucleus spinalis nervi trigemini, motor nuclei of certain cranial nerves, nucleus commissuralis and formatio reticularis; and in the spinal cord the substantia gelatinosa. In contrast enkephalin cell bodies appear sparsely distributed in the telencephalon, diencephelon, mensencephalon and rhombencephalon. The results of the histochemical staining show that certain structures which positively stain for enkephalin closely correspond to the distribution of opiate receptors in the brain and thus support the concept that the endogenous opiate peptides are involved in the perception of pain and analgesia. The localization of enkephalin in the preoptic-hypothalamic region together with the presence of enkephalin perikarya in the paraventricular and supraoptic nuclei suggest a role of enkephalin in the regulation of neuroendocrine functions.

Immunohistochemical localization of enkephalin in rat brain and spinal cord.

A model of fear and pain is presented in which the two are assumed to activate totally different classes of behavior. Fear, produced by stimuli that are associated with painful events, results in defensive behavior and the inhibition of pain and pain-related behaviors. On the other hand, pain, produced by injurious stimulation, motivates recuperative behaviors that promote healing. In this model injurious stimulation, on the one hand, and the expectation of injurious stimulation, on the other hand, activate entirely different motivational systems which serve entirely different functions. The fear motivation system activates defensive behavior, such as freezing and flight from a frightening situation, and its function is to defend the animal against natural dangers, such as predation. A further effect of fear motivation is to organize the perception of environmental events so as to facilitate the perception of danger and safety. The pain motivation system activates recuperative behaviors, including resting and body-care responses, and its function is to promote the animal's recovery from injury. Pain motivation also selectively facilitates the perception of nociceptive stimulation. Since the two kinds of motivation serve different and competitive functions, it might be expected that they would interact through some kind of mutual inhibition. Recent research is described which indicates that this is the case. The most important connection is the inhibition of pain by fear; fear has the top priority. This inhibition appears to be mediated by an endogenous analgesic mechanism involving the endorphins. The model assumes that fear triggers the endorphin mechanism, thereby inhibiting pain motivation and recuperative behaviors that might compete with effective defensive behavior.

A perceptual-defensive-recuperative model of fear and pain

ENKEPHALIN, a natural opiate receptor agonist in brain1–4, has been identified by Hughes et al.5 as a mixture of two pentapeptides : H–Tyr–Gly–Gly–Phe–Met–OH (methionine–enkephalin) and H–Tyr–Gly–Gly–Phe–Leu–OH (leucine–enkephalin). Both peptides mimic the ability of morphine to block electrically evoked contractions of mouse vas deferens and guinea pig ileum, and both inhibit the stereospecific receptor binding of the opiate antagonist 3H-naloxone in brain homogenates5. On the basis of this and other6–8 evidence, it has been proposed2,9,10 that enkephalin receptors may be sites at which morphine-like drugs exert their analgesic actions, and that the enkephalins themselves may be modulators or transmitters in brain systems for pain suppression or analgesia. Consistently with this suggestion, we find that methionine–enkephalin and leucine–enkephalin, when administered through permanently indwelling cannulae in the lateral ventricles of rats, induce a profound analgesia in vivo that is fully reversible by naloxone.

Analgesia induced in vivo by central administration of enkephalin in rat

ENKEPHALIN, an endogenous pentapeptide which has the analgesic properties of morphine1, has recently been isolated, purified and characterised both chemically and pharmacologically2,3. The fact that enkephalin and the opiates interact with the same receptor raises the possibility that the similarity in their function might be based on common structural features4,5. Particular attention has been paid to the geometric relationship between the aromatic ring of the tyrosine residue and the terminal amino group of enkephalin compared with the known geometry of similar functional groups in morphine. The relative spatial disposition of the phenylalanine and tyrosine aromatic side chains is also of special interest because of the possible resemblance of enkephalin to oripavine4,5. So far, however, no experimental determination of conformational parameters has appeared. Here we report proton magnetic resonance (PMR) studies of Met5-enkephalin which indicate that the methionine amino proton is involved in a hydrogen bond, most probably within a Gly–Gly–Phe–Met type I β turn, but not with a turn involving Tyr–Gly–Gly–Phe as proposed previously6. Although our data exclude a γ turn, they do not rigorously exclude other conformations, especially if these have small statistical weights.

Proton magnetic resonance studies of conformation and flexibility of enkephalin peptides.

Enkephalin-stimulated prolactin release.

Dissociation of somatostatin effects. Peptides inhibiting the release of growth hormone but not glucagon or insulin in rats

The growth hormone release inhibiting undecapeptide of the formula Nα-(3-mercaptopropionyl)-L-Lys-L-Asn-L-Phe-L-Phe-L-Trp-L-Lys-L-Thr-L- Phe-L-Thr-L-Ser-L-Cys cyclic (1-11) disulfide.

Victor Garsky

Papers

Analgesia induced in vivo by central administration of enkephalin in rat

Proton magnetic resonance studies of conformation and flexibility of enkephalin peptides.

Enkephalin-stimulated prolactin release.

Dissociation of somatostatin effects. Peptides inhibiting the release of growth hormone but not glucagon or insulin in rats

[Des-Ala1, Gly2 -desamino-Cys3 ]somatostatin