Molecular cloning and tissue distribution of a receptor for pituitary adenylate cyclase-activating polypeptide

doi:10.1016/0896-6273(93)90188-W

Neuron

Volume 11, Issue 2, August 1993, Pages 333-342

https://doi.org/10.1016/0896-6273(93)90188-W Get rights and content

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a polypeptide hormone related to vasoactive intestinal polypeptide (VIP). Rat PACAP receptor cDNA was isolated from a brain cDNA library by cross-hybridization with rat VIP receptor cDNA. The recombinant PACAP receptor expressed in COS cells bound PACAP with about 1000 times higher affinity than VIP, and PACAP stimulated adenylate cyclase through the cloned PACAP receptor. The rat PACAP receptor consists of 495 amino acids, contains seven transmembrane segments, and has a significant similarity with other G_s-coupled receptors, such as VIP, glucagon, and secretin receptors. PACAP receptor mRNA was abundantly expressed in the brain, but not in the peripheral tissues except for the adrenal gland. In situ hybridization revealed a high level of expression of PACAP receptor mRNA in the hippocampal dentate gyrus, olfactory bulb, and cerebellar cortex.

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Pituitary adenylate cyclase-activating peptide (PACAP) and its receptors in Mus musculus testis
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To enlighten the involvement of PACAP/receptors system in the control of mammal testis, we investigated the expression of PACAP and the localization of PACAP and its receptors PAC1, VPAC1, and VPAC2 in the testis of Mus musculus. By molecular and immunohistochemical investigations, we highlighted that PACAP and its receptors are widely represented in germ cells of Mus testis, particularly in spermatocytes I, spermatids, and spermatozoa, strongly suggesting their involvement in spermatogenesis process. Moreover, for the first time in the adult mouse testis we highlighted that PACAP is present within Leydig cells, as PACAP receptors, confirming its involvement in the control of steroidogenesis in mouse.
Pituitary adenylate cyclase-activating polypeptide (PACAP) in stress, pain, and learning
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Citation Excerpt :
PACAP is widely expressed throughout the periphery and central nervous system, and within the brain PACAP-38 is the predominant form (Arimura et al., 1991; Miyata et al., 1989; Miyata et al., 1990; Piggins, Stamp, Burns, Rusak, & Semba, 1996; Vaudry et al., 2009). PACAP influences cellular function through G-protein-coupled receptors: the PACAP receptor type I (PAC1R), which is highly selective for PACAP, and through VIP receptors (VPAC1 and VPAC2), which can be activated by PACAP or VIP (Harmar et al., 1998; Hashimoto, Ishihara, Shigemoto, Mori, & Nagata, 1993; Ishihara, Shigemoto, Mori, Takahashi, & Nagata, 1992; Lutz, Shen, Mackay, West, & Harmar, 1999). PACAP has been described as the “master regulator” of the stress response, based on its role in stimulating the biosynthesis of corticotropin-releasing factor in the hypothalamus (Hashimoto, Shintani, & Baba, 2006; Mustafa, 2013; Stroth, Holighaus, Ait-Ali, & Eiden, 2011).
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide, which has been linked in both rodents and humans to stress, anxiety, and fear. PACAP signaling within the hypothalamo-pituitary-adrenocortical (HPA axis) and limbic structures mediates many of the physiological and emotional responses to chronic stress, and genetic abnormality of PAC1R signaling in humans has been linked to pathological stress and fear in post-traumatic stress disorder and major depressive disorder. PACAP modulates neuronal excitability and synaptic transmission through Gαs- and Gαq-coupled receptors and through functional interaction with glutamate receptors. In this chapter we discuss how PACAP exerts circuit- and receptor-specific modulation of anxiety, pain, aversive learning, and stress-related behavior. We also discuss sex differences in PACAP-mediated function, the link to stress disorders, and highlight the emerging data establishing the amygdala as a key site of action for PACAP.
Role of endogenous pituitary adenylate cyclase activating polypeptide (PACAP) in myelination of the rodent brain: Lessons from PACAP-deficient mice
2011, International Journal of Developmental Neuroscience
Pituitary adenylate-cyclase activator polypeptide (PACAP), as a consequence of its effect on the elevation of intracellular cAMP level, strongly influences brain development including myelination. While proliferation of oligodendroglial progenitors is stimulated by PACAP applied in vitro, their differentiation is inhibited. However, the in vivo role of PACAP on myelination has never been examined.
In the present study the role of endogenous PACAP in myelination was examined in PACAP-deficient mice, in several areas of the brain with a special attention to the cerebral cortex. In young postnatal and adult mice myelination was studied with immunohistochemistry detecting a protein present in the myelin sheath, the myelin basic protein, with Luxol Fast Blue staining and with electron microscopy. Results obtained in PACAP-deficient mice were compared to age-matched wild type controls.
We found that the sequence of myelination in the PACAP-deficient animals was similar to that observed in controls. According to this, in both PACAP-deficient and wild type mice, the somatosensory cortex was myelinated before motor areas that preceded the myelination of associational cortical areas. Archicortical associational areas such as the cingulate cortex were myelinated before neocortical areas. Myelination in the corpus callosum followed the known rostro-caudal direction in both PACAP-deficient and wild type animals, and the ventrolateral part of the corpus callosum was myelinated earlier than the dorsomedial part in both groups. In contrast to the similarity in its sequence, striking difference was found in the onset of myelination that started earlier in PACAP-deficient mice than in wild type controls in all of the examined brain regions, including cerebral archi- and neocortex. The first myelinated axons in each of the examined brain regions were observed earlier in the PACAP-deficient mice than in controls. When age-matched animals of the two groups were compared, density of myelinated fibers in the PACAP-deficient mice was higher than in controls in all of the examined areas.
We propose that endogenous PACAP exerts an inhibitory role on myelination in vivo. Since myelin sheath of the central nervous system contains several factors blocking neurite outgrowth, inhibition of myelination by PACAP gives time for axonal development and synapse formation, and therefore, strengthens neuronal plasticity.
The role of PACAP in central cardiorespiratory regulation
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Pituitary adenylate cyclase activating polypeptide (PACAP) plays a role in almost every biological process from reproduction to hippocampal function. One area where a role for PACAP is not clearly delineated is central cardiorespiratory regulation. PACAP and its receptors (PAC1, VPAC1 and VPAC2) are present in cardiovascular areas of the ventral medulla and spinal cord and in the periphery. Central administration of PACAP generally increases arterial pressure. Knowledge about the role of PACAP in central cardiovascular regulation is growing, but even less is known about PACAP in central respiratory regulation. No specific data is currently available regarding the presence of PACAP or receptors in key respiratory centers, although it is known that neonatal PACAP knock-out mice die suddenly in a manner similar to sudden infant death syndrome (SIDS). Future studies in mature preparations investigating the role of PACAP in the physiology and integration of central cardiorespiratory reflexes are clearly essential for a full understanding of this important neuropeptide in breathing.
Pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC <inf>1</inf>HOP1 receptor activation coordinates multiple neurotrophic signaling pathways: Akt activation through phosphatidylinositol 3-kinase γ and vesicle endocytosis for neuronal survival
2010, Journal of Biological Chemistry
Citation Excerpt :
Two α-amidated forms of PACAP arise from alternative post-translational processing of the 175-amino acid rat precursor molecule; PACAP38 has 38 amino acid residues (proPACAP-(131–168)), whereasPACAP27 corresponds to the amino terminus of PACAP38 (proPACAP-(131–157)). As PACAP and VIP appear to stem from the same molecular cladistic tree during evolution (1), the two peptides not only share considerable structural homology but also function through three distinct G protein-coupled receptors (2–8). Only PACAP peptides exhibit high affinity for the PAC1 receptor, whereas VIP and PACAP have similar high affinities for the VPAC1 and VPAC2 receptors.
MAPK and Akt pathways are predominant mediators of trophic signaling for many neuronal systems. Among the vasoactive intestinal peptide/secretin/glucagon family of related peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) binding to specific PAC₁ receptor isoforms can engage multiple signaling pathways and promote neuroprotection through mechanisms that are not well understood. Using a primary sympathetic neuronal system, the current studies demonstrate that PACAP activation of PAC₁HOP1 receptors engages both MAPK and Akt neurotrophic pathways in an integrated program to facilitate neuronal survival after growth factor withdrawal. PACAP not only stimulated prosurvival ERK1/2 and ERK5 activation but also abrogated SAPK/JNK and p38 MAPK signaling in parallel. In contrast to the potent and rapid effects of PACAP in ERK1/2 phosphorylation, PACAP stimulated Akt phosphorylation in a late phase of PAC₁HOP1 receptor signaling. From inhibitor and immunoprecipitation analyses, the PACAP/PAC₁HOP1 receptor-mediated Akt responses did not represent transactivation mechanisms but appeared to depend on Gα_q/phosphatidylinositol 3-kinase γ activity and vesicular internalization pathways. Phosphatidylinositol 3-kinase γ-selective inhibitors blocked PACAP-stimulated Akt phosphorylation in primary neuronal cultures and in PAC₁HOP1-overexpressing cell lines; RNA interference-mediated knockdown of the receptor effectors attenuated PACAP-mediated Akt activation. Similarly, perturbation of endocytic pathways also blocked Akt phosphorylation. Between ERK and Akt pathways, PACAP-stimulated Akt signaling was the primary cascade that attenuated cultured neuron apoptosis after growth factor withdrawal. The partitioning of PACAP-mediated Akt signaling in endosomes may be a key mechanism contributing to the high spatial and temporal specificity in signal transduction necessary for survival pathways.
Hypothalamic PACAP/PAC1R Involvement in Feeding and Body Weight Regulation
2023, Endocrinology (United States)

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^‡: Present address: DNA Research Center, National Institute of Genetics, Mishima, Shizuoka 411, Japan.

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Neuron

ArticleMolecular cloning and tissue distribution of a receptor for pituitary adenylate cyclase-activating polypeptide

Abstract

Neurosci. Lett.

FEBS Lett.

Anal. Biochem.

J. Biol. Chem.

J. Biol. Chem.

Neuron

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Mol. Biol.

Brain Res.

Brain Res.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Anal. Biochem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Neuroscience

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Article
Molecular cloning and tissue distribution of a receptor for pituitary adenylate cyclase-activating polypeptide