PACAP Signaling
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PACAP Signaling
PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide) is a member of the secretin glucagon-VIP (Vasoactive Intestinal Peptide) family of peptides and is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, and respiratory and urogenital tracts. Within the CNS, PACAP serves as a neurotransmitter, neurohormone, neuromodulator, secretagogue, neurotrophic factor, neuroprotectant, and glial effector. The effects of PACAP are mediated through three types of GPCR (G-Protein Coupled Receptors): VPAC1 and VPAC2 receptors (Type-II) bind PACAP and VIP with equal affinities, while PACAPR (Type-I; PACAP Receptor) specifically binds PACAP with high affinity. PACAPR is particularly abundant in the brain and pituitary and adrenal glands whereas VPAC receptors are expressed mainly in the lung, liver, and testis (Ref.1).

The PACAP precursor molecule exists in two biologically active forms, PACAP27 and PACAP38, of which PACAP27 is an N-terminally truncated form of PACAP38. PACAP exerts an array of growth factor-like actions that depend on the source and developmental stage of the cells. It promotes survival and induces neurite sprouting of neuroblast cells. Such neurotrophic effects are mediated through the G-protein (G-AlphaS and G-AlphaQ) dependent AC (Adenylyl Cyclase) pathway via PKA (Protein Kinase-A), MAP Kinases (MAP3Ks and MAP2Ks), ERK1/2 (Extracellular Signal-Regulated Kinases) or CBP (CREB-Binding Protein) and CREB (CRE-Binding Protein) phosphorylation, which results in increased c-Fos mediated gene expression. c-Fos proteins can also complex with members of CREB/ATF1 (Activating Transcription Factor-1) and bind similar but distinct sequences termed CRE (cAMP Responsive Element), respectively. Activation of PACAPR by PACAP also leads to activation of PLC (Phospholipase-C)-PIP2 (Phosphatidyl Inositol 4, 5-Bisphosphate) dependent IP3 (Inositol 1, 4, 5-Trisphosphate) production along with DAG (Diacylglycerol). IP3 binds to its intracellular receptor (IP3R), a ligand-gated Ca2+ channel located in the endoplasmic reticulum, and triggers the release of Ca2+ from internal stores. In the pituitary gland, both PKA (Protein Kinase-A) and PKC (Protein Kinase-C) are involved in the PACAP-induced Ca2+ entry mechanism (Ref.2&3). PACAP also increases expression of neuropeptide genes through separate cAMP (Cyclic Adenosine 3, 5-monophosphate) and Ca2+ signaling pathways.

Like other hypophysiotropic neurohormones, PACAP is present in extra-hypothalamic neurons as well as in numerous peripheral tissues. Consistent with its widespread distribution, PACAP exerts pleiotropic effects including modulation of neurotransmitter release, vasodilation, bronchodilation, and activation of intestinal motility, increase of insulin and histamine secretion, as well as stimulation of cell multiplication and/or differentiation. PACAP has now been shown to act as a hormone, a neurohormone, a neurotransmitter, and a trophic factor in a number of tissues. In the pancreas, PACAP is localized to nerves surrounding the blood vessels, the exocrine parenchyma and in conjunction with the endocrine islets. It is released from parasympathetic nerves upon food intake, and, by increasing the levels of cAMP in pancreatic Beta-cells; PACAP potentiates glucose-stimulated insulin secretion (Ref.4).