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

During the last decade, the GH axis has become the compelling focus of remarkably active and broad-ranging basic and clinical research. Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts. The complexity of the GHRH/somatostatin-GH-IGF-I axis thus commends itself to more formalized modeling (154, 155), since the multivalent feedback-control activities are difficult to assimilate fully on an intuitive scale. Understanding the dynamic neuroendocrine mechanisms that direct the pulsatile secretion of this fundamental growth-promoting and metabolic hormone remains a critical goal, the realization of which is challenged by the exponentially accumulating matrix of experimental and clinical data in this arena. To the above end, we review here the pathophysiology of the GHRH somatostatin-GH-IGF-I feedback axis consisting of corresponding key neurotransmitters, neuromodulators, and metabolic effectors, and their cloned receptors and signaling pathways. We propose that this system is best viewed as a multivalent feedback network that is exquisitely sensitive to an array of neuroregulators and environmental stressors and genetic restraints. Feedback and feedforward mechanisms acting within the intact somatotropic axis mediate homeostatic control throughout the human lifetime and are disrupted in disease. Novel effectors of the GH axis, such as GHRPs, also offer promise as investigative probes and possible therapeutic agents. Further understanding of the mechanisms of GH neuroregulation will likely allow development of progressively more specific molecular and clinical tools for the diagnosis and treatment of various conditions in which GH secretion is regulated abnormally. Thus, we predict that unexpected and enriching insights in the domain of the neuroendocrine pathophysiology of the GH axis are likely be achieved in the succeeding decades of basic and clinical research.

Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human

The two forms of pituitary adenylyl cyclase-activating polypeptide (PACAP-27 and -38) are neuropeptides of the secretin/glucagon/vasoactive intestinal polypeptide/growth-hormone-releasing hormone family and regulate hormone release from the pituitary and adrenal gland. They may also be involved in spermatogenesis, and PACAP-38 potently stimulates neuritogenesis and survival of cultured rat sympathetic neuroblast and promotes neurite outgrowth of PC-12 cells. The PACAP type-I receptor (found in hypothalamus, brain stem, pituitary, adrenal gland and testes), specific for PACAP, is positively coupled to adenylyl cyclase and phospholipase C. The recently cloned type II receptor does not discriminate between PACAP and vasoactive intestinal polypeptide and is coupled to only adenylyl cyclase. Here we have used a new expression cloning strategy, based on the induction of a reporter gene by cyclic AMP, to isolate a complementary DNA encoding the type-I PACAP receptor. On transfection of this cDNA, both PACAP-27 and -38 stimulate adenylyl cyclase with similar EC50 values (50% effective concentration, 0.1-0.4 nM), whereas only PACAP-38 stimulates phospholipase C with high potency (EC50 = 15 nM). Four other splice variants were isolated with insertions at the C-terminal end of the third intracellular loop. Expression of these cDNAs revealed altered patterns of adenylyl cyclase and phospholipase C stimulation, suggesting a novel mechanism for fine tuning of signal transduction.

Differential signal transduction by five splice variants of the PACAP receptor

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was first isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP formation in anterior pituitary cells. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-glucagon-growth hormone releasing factor-secretin superfamily. The sequence of PACAP has been remarkably well conserved during the evolution from protochordate to mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, and respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide whose activity remains unknown. Two types of PACAP binding sites have been characterized. Type I binding sites exhibit a high affinity for PACAP and a much lower affinity for VIP whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes, the PACAP-specific PAC1 receptor, which is coupled to several transduction systems, and the two PACAP/VIP-indifferent VPAC1 and VPAC2 receptors, which are primarily coupled to adenylyl cyclase. PAC1 receptors are particularly abundant in the brain and pituitary and adrenal glands whereas VPAC receptors are expressed mainly in the lung, liver, and testis. The wide distribution of PACAP and PACAP receptors has led to an explosion of studies aimed at determining the pharmacological effects and biological functions of the peptide. This report reviews the current knowledge concerning the multiple actions of PACAP in the central nervous system and in various peripheral organs including the endocrine glands, the airways, and the cardiovascular and immune systems, as well as the different effects of PACAP on a number of tumor cell types.

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: From Structure to Functions

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid C-terminally alpha-amidated peptide that was first isolated 20 years ago from an ovine hypothalamic extract on the basis of its ability to stimulate cAMP formation in anterior pituitary cells (Miyata et al., 1989. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-secretin-growth hormone-releasing hormone-glucagon superfamily. The sequence of PACAP has been remarkably well conserved during evolution from protochordates to mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide, the activity of which remains unknown. Two types of PACAP binding sites have been characterized: type I binding sites exhibit a high affinity for PACAP and a much lower affinity for VIP, whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes: the PACAP-specific PAC1-R, which is coupled to several transduction systems, and the PACAP/VIP-indifferent VPAC1-R and VPAC2-R, which are primarily coupled to adenylyl cyclase. PAC1-Rs are particularly abundant in the brain, the pituitary and the adrenal gland, whereas VPAC receptors are expressed mainly in lung, liver, and testis. The development of transgenic animal models and specific PACAP receptor ligands has strongly contributed to deciphering the various actions of PACAP. Consistent with the wide distribution of PACAP and its receptors, the peptide has now been shown to exert a large array of pharmacological effects and biological functions. The present report reviews the current knowledge concerning the pleiotropic actions of PACAP and discusses its possible use for future therapeutic applications.

Naoto Minamino

Papers

Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells

Biological and immunological characterization of corticotropin-releasing activity in the bovine adrenal medulla.

Chemical characterization of angiotensin I in porcine follicular fluid.