PACAP is a pleiotropic neuropeptide that belongs to the secretin/glucagon/VIP family. PACAP functions as a hypothalamic hormone, neurotransmitter, neuromodulator, vasodilator, and neurotrophic factor. Its structure has been remarkably conserved during evolution. The PACAP receptor is G protein-coupled with seven transmembrane domains and also belongs to the VIP receptor family. PACAP, but not VIP, binds to PAC1-R, whereas PACAP and VIP bind to VPAC1-R and VPAC2-R with a similar affinity. Despite the sizable homology of the structures of PACAP and VIP and their receptors, the distribution of these peptides and receptors is quite different. At least eight subtypes of PACAP specific, or PAC1-R, result from alternate splicing. Each subtype is coupled with specific signaling pathways, and its expression is tissue or cell specific. Although PACAP fulfills most requirements for a physiological hypothalamic hypophysiotropic hormone, it does not consistently stimulate secretion of the adenohypophysial hormones, except for stimulation of IL-6 release from the FS cells of the pituitary. The major regulatory role of PACAP in pituitary cells appears to be the regulation of gene expression of pituitary hormones and/or regulatory proteins that control growth and differentiation of the pituitary glandular cells. These effects appear to be exhibited directly and indirectly through a paracrine or autocrine action. Although PACAP stimulates the release of AVP, the physiological role of neurohypophysial PACAP remains unknown. One important action of PACAP in the endocrine system is its role as a potent secretagogue for adrenaline from the adrenal medulla through activation of TH. PACAP also stimulates the release of insulin and increases [Ca2+]i from pancreatic beta-cells at an extremely small concentration. The stage-specific expression of PACAP in testicular germ cells during spermatogenesis suggests its regulatory role in the maturation of germ cells. In the ovary, PACAP is transiently expressed in the granulosa cells of the preovulatory follicles and appears to be involved in the LH-induced cellular events in the ovary, including prevention of follicular apoptosis. In the central nervous system, PACAP acts as a neurotransmitter or neuromodulator, which has been supported by IHC and electrophysiological methods. More important, PACAP is a neurotrophic factor that may play an important role during the development of the brain. In the adult brain, PACAP appears to function as a neuroprotective factor that attenuates the neuronal damage resulting from various insults.

Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems.

Many bioactive peptides must be amidated at their carboxy terminus to exhibit full activity Surprisingly, the amides are not generated by a transamidation reaction Instead, the hormones are synthesized from glycine-extended intermediates that are transformed into active amidated hormones by oxidative cleavage of the glycine N-Cα bond In higher organisms, this reaction is catalyzed by a single bifunctional enzyme, peptidylglycine α-amidating monooxygenase (PAM) The PAM gene encodes one polypeptide with two enzymes that catalyze the two sequential reactions required for amidation Peptidylglycine α-hydroxylating monooxygenase (PHM; EC 114173) catalyzes the stereospecific hydroxylation of the glycine α-carbon of all the peptidylglycine substrates The second enzyme, peptidyl-α-hydroxyglycine α-amidating lyase (PAL; EC 4325), generates α-amidated peptide product and glyoxylate PHM contains two redox-active copper atoms that, after reduction by ascorbate, catalyze the reduction of molecular oxygen for the hydroxylation of glycine-extended substrates The structure of the catalytic core of rat PHM at atomic resolution provides a framework for understanding the broad substrate specificity of PHM, identifying residues critical for PHM activity, and proposing mechanisms for the chemical and electron-transfer steps in catalysis Since PHM is homologous in sequence and mechanism to dopamine β-monooxygenase (DBM; EC 114171), the enzyme that converts dopamine to norepinephrine during catecholamine biosynthesis, these structural and mechanistic insights are extended to DBM

New insights into copper monooxygenases and peptide amidation: structure, mechanism and function.

I. Introduction PITUITARY adenylate cyclase activating polypeptide (PACAP) was first isolated from ovine hypothalamus by its potent activity in stimulating cAMP production in rat anterior pituitary cells (1). Since its isolation a wealth of literature has been published describing its activity in a variety of tissues including pituitary, brain, adrenal, testis, and in the nerve fibers of both the gut and the lung. A number of reviews have discussed its actions in a variety of cell types (2–4), its binding sites (5), and the characteristics of the three PACAP receptors cloned to date, two of which it apparently shares with vasoactive intestinal polypeptide (VIP) (4, 6, 7). The present review will deal specifically with the putative role of PACAP as a hypophysiotropic factor regulating anterior pituitary cell activity: This review begins with a brief history of PACAP and a description of its structure and its receptors. We will then discuss the distribution of PACAP in the hypothalamus, which suggests its r...

Pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP/vasoactive intestinal polypeptide receptors: actions on the anterior pituitary gland.

Pituitary adenylate cyclase-activating polypeptides (PACAP-27 and PACAP-38) are neuropeptides of the vasoactive intestinal polypeptide (VIP)/secretin/glucagon family. PACAP receptors are expressed in different brain regions, including cerebellum. We used primary culture of rat cerebellar granule neurons to study the effect of PACAP-38 on apoptosis induced by potassium deprivation. We demonstrated that PACAP-38 increased survival of cerebellar neurons in a dose-dependent manner by decreasing the extent of apoptosis estimated by DNA fragmentation. PACAP-38 induced activation of the extracellular signal-regulated kinase (ERK)-type of mitogen-activated protein (MAP) kinase through a cAMP-dependent pathway. PD98059, an inhibitor of MEK (MAP kinase kinase), completely abolished the antiapoptotic effect of PACAP-38, suggesting that MAP kinase pathway activation is necessary for PACAP-38 action.

https://www.jneurosci.org/content/jneuro/17/1/83.full.pdf

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP-38) Protects Cerebellar Granule Neurons from Apoptosis by Activating the Mitogen-Activated Protein Kinase (MAP Kinase) Pathway

Prevention of ischemia-induced death of hippocampal neurons by pituitary adenylate cyclase activating polypeptide.

In addition to classical neurotrophic factors, neurotransmitters and neuropeptides also exhibit neurotrophic activities.' The central nervous system (CNS) contains a variety of neuropeptides in neurons and nonneuronal cells. These peptides and their receptors appear in early developmental stages, often transiently expressed at a peak level, suggesting a possible physiological role as modulators of growth and differentiation of neurons. Neurotrophic actions of a number of neuropeptides have been reported. In particular, vasoactive intestinal peptide (VIP), which is a preganglionic neurotransmitter in the sympathetic nervous system of the adult rat,* was shown to exert multiple actions on developing sympathetic neuroblasts in culture, including stimulation of neuronal mitosis, survival, and process o~tgrowth .~ VIP also increases the survival of cultured spinal cord neurons during a critical period of de~elopment .~ .~ Pituitary adenylate cyclase activating polypeptide (PACAP) was first isolated from ovine hypothalamic tissues during an attempt to isolate a novel hypophysiotropic hormone based on the ability to activate adenylate cyclase in rat pituitary cell cultures. Two forms of PACAP, one with 38 residues (PACAP38) and a truncated form with 27 residues (PACAP27), were isolated from the ovine hypothalamic PACAP is a new member of secretin-glucagon-VIP family with 60% sequence homology with VIP, but its adenylate cyclase stimulating activity in cultured pituitary cells is 1000 times greater than Immunohistochemical

R. C. Fiore

Papers

PACAP Functions as a Neurotrophic Factor