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Pituitary adenylate cyclase activating polypeptide (PACAP), stress, and sex hormones.

ABSTRACT: Stressor exposure is associated with the onset and severity of many psychopathologies that are more common in women than men. Moreover, the maladaptive expression and function of stress-related hormones have been implicated in these disorders. Evidence suggests that PACAP has a critical role in the stress circuits mediating stress-responding, and PACAP may interact with sex hormones to contribute to sex differences in stress-related disease. In this review, we describe the role of the PACAP/PAC1 system in stress biology, focusing on the role of stress-induced alterations in PACAP expression and signaling in the development of stress-induced behavioral change. Additionally, we present more recent data suggesting potential interactions between stress, PACAP, and circulating estradiol in pathological states, including PTSD. These studies suggest that the level of stress and circulating gonadal hormones may differentially regulate the PACAPergic system in males and females to influence anxiety-like behavior and may be one mechanism underlying the discrepancies in human psychiatric disorders.

SUBMITTER: King SB

PROVIDER: S-EPMC6724739 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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Pituitary adenylate cyclase activating polypeptide (PACAP), stress, and sex hormones.

King S Bradley SB Toufexis Donna J DJ Hammack Sayamwong E SE

Stress (Amsterdam, Netherlands) 20170614 5

Stressor exposure is associated with the onset and severity of many psychopathologies that are more common in women than men. Moreover, the maladaptive expression and function of stress-related hormones have been implicated in these disorders. Evidence suggests that PACAP has a critical role in the stress circuits mediating stress-responding, and PACAP may interact with sex hormones to contribute to sex differences in stress-related disease. In this review, we describe the role of the PACAP/PAC1 ...[more]

PMID: 28610473

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Project description:Pituitary adenylate cyclase activating polypeptide (PACAP) is a well-conserved neuropeptide characteristic of vertebrates. This pluripotent hypothalamic neuropeptide regulates neurotransmitter release, intestinal motility, metabolism, cell division/differentiation, and immunity. In vertebrates, PACAP has a specific receptor (PAC1) but it can also activate the Vasoactive Intestinal Peptide receptors (VPAC1 and VPAC2). The evolution of the vertebrate PACAP ligand - receptor pair has been well-described. In contrast, the situation in invertebrates is much less clear. The PACAP ligand - receptor pair in invertebrates has mainly been studied using heterologous antibodies raised against mammalian peptides. A few partial PACAP cDNA clones sharing >87% aa identity with vertebrate PACAP have been isolated from a cnidarian, several protostomes and tunicates but no gene has been reported. Moreover, current evolutionary models of the peptide and receptors using molecular data from phylogenetically distinct invertebrate species (mostly nematodes and arthropods) suggests the PACAP ligand and receptors are exclusive to vertebrate genomes. A basal deuterostome, the cephalochordate amphioxus (Branchiostoma floridae), is the only invertebrate in which elements of a PACAP-like system exists but the peptides and receptor share relatively low sequence conservation with the vertebrate homolog system and are a hybrid with the vertebrate glucagon system. In this study, the evolution of the PACAP system is revisited taking advantage of the burgeoning sequence data (genome and transcriptomes) available for invertebrates to uncover clues about when it first appeared. The results suggest that elements of the PACAP system are absent from protozoans, non-bilaterians, and protostomes and they only emerged after the protostome-deuterostome divergence. PACAP and its receptors appeared in vertebrate genomes and they probably shared a common ancestral origin with the cephalochordate PACAP/GCG-like system which after the genome tetraploidization events that preceded the vertebrate radiation generated the PACAP ligand and receptor pair and also the other members of the Secretin family peptides and their receptors.

Project description:Pituitary adenylate cyclase-activating polypeptide (PACAP) promotes neurite outgrowth and inhibits proliferation of rat pheochromocytoma (PC12) cells. Characterizing the PACAP-differentiated PC12 cell transcriptome should provide genetic insight into how these processes occur in these cells, and in neuronal precursors in vivo. For this purpose, RNA samples were collected from PC12 cells before or after a 6-h treatment with PACAP, from which a labeled cDNA was hybridized to a high-density cDNA array containing 15 365 genes. The genomic response to PACAP involves at least 73 genes. Among the genes differentially expressed in the presence of PACAP, 71% were up regulated, and 29% down regulated, 2-fold or more. Sixty-six percent of the messages affected by PACAP code for functionally categorized proteins, most not previously known to be regulated during PC12 cell differentiation. PACAP has been shown to induce PC12 cell neurite outgrowth through the mitogen-activated protein kinase kinase (MEK) pathway independently of protein kinase A (PKA). Therefore treatments were conducted in the absence or presence of the PKA inhibitor H89, or the MEK inhibitor U0126 in order to identify subsets of genes involved in specific aspects of PC12 cell differentiation. Co-treatment of PC12 cells with PACAP plus H89 revealed a cluster of five genes specifically regulated through the PKA pathway and co-treatment of the cells with PACAP and U0126 revealed a cluster of 13 messages specifically activated through the MEK pathway. Many of the known genes regulated by PACAP have been associated with neuritogenesis (i.e. villin 2 or annexin A2) or cell growth (i.e. growth arrest specific 1 or cyclin B2). Thus, some of the expressed sequence tags (ESTs) that exhibit the same regulation pattern (i.e. AU016391 or AW552690) may also be involved in the neuritogenic and anti-mitogenic effects of PACAP in PC12 cells. Among the 73 PACAP regulated genes, 10 are disqualified on pharmacological grounds as actors in PACAP-mediated neurite outgrowth or growth arrest, leaving 63 new PACAP-regulated genes implicated in neuronal differentiation. Thirteen of these are candidates for mediating ERK-dependent neurite outgrowth, and 47 are possibly involved in the ERK-independent growth arrest induced by PACAP.

Dataset Information

Pituitary adenylate cyclase activating polypeptide (PACAP), stress, and sex hormones.

Publications

Pituitary adenylate cyclase activating polypeptide (PACAP), stress, and sex hormones.

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