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      Alternative Splicing of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor PAC1: Mechanisms of Fine Tuning of Brain Activity

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          Abstract

          Alternative splicing of the precursor mRNA encoding for the neuropeptide receptor PAC1/ADCYAP1R1 generates multiple protein products that exhibit pleiotropic activities. Recent studies in mammals and zebrafish have implicated some of these splice isoforms in control of both cellular and body homeostasis. Here, we review the regulation of PAC1 splice variants and their underlying signal transduction and physiological processes in the nervous system.

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          Calcium signaling.

          David E Clapham, Md. Islam (2008)
          Calcium ions (Ca(2+)) impact nearly every aspect of cellular life. This review examines the principles of Ca(2+) signaling, from changes in protein conformations driven by Ca(2+) to the mechanisms that control Ca(2+) levels in the cytoplasm and organelles. Also discussed is the highly localized nature of Ca(2+)-mediated signal transduction and its specific roles in excitability, exocytosis, motility, apoptosis, and transcription.
          Article 0 comments Cited 1264 times – based on 0 reviews     Review now
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            Heterotrimeric G protein activation by G-protein-coupled receptors.

            William M Oldham, Heidi Hamm (2008)
            Heterotrimeric G proteins have a crucial role as molecular switches in signal transduction pathways mediated by G-protein-coupled receptors. Extracellular stimuli activate these receptors, which then catalyse GTP-GDP exchange on the G protein alpha-subunit. The complex series of interactions and conformational changes that connect agonist binding to G protein activation raise various interesting questions about the structure, biomechanics, kinetics and specificity of signal transduction across the plasma membrane.
            Article 0 comments Cited 348 times – based on 0 reviews     Review now
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              Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor

              Kerry Ressler, Kristina B Mercer, Bekh Bradley … (2011)
              Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP/PAC1 receptor pathway has a role in human psychological stress responses, such as posttraumatic stress disorder (PTSD). In heavily traumatized subjects, we find a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females (N=64, replication N=74, p<0.005). Using a tag-SNP genetic approach (44 single nucleotide polymorphisms, SNPs) spanning the PACAP (ADCYAP1) and PAC1 (ADCYAP1R1) genes, we find a sex-specific association with PTSD. rs2267735, a SNP in a putative estrogen response element within ADCYAP1R1, predicts PTSD diagnosis and symptoms in females only (combined initial and replication samples: N=1237; p<2x10 − 5). This SNP also associates with fear discrimination and with ADCYAP1R1 mRNA expression. Methylation of ADCYAP1R1 is also associated with PTSD (p < 0.001). Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or estrogen replacement in rodent models. These data suggest that perturbations in the PACAP/PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via estrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.
              Article 0 comments Cited 253 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Front Endocrinol (Lausanne)
                Journal ID (iso-abbrev): Front Endocrinol (Lausanne)
                Journal ID (publisher-id): Front. Endocrinol.
                Title: Frontiers in Endocrinology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-2392
                Publication date (Electronic): 21 May 2013
                Publication date Collection: 2013
                Volume: 4
                Electronic Location Identifier: 55
                Affiliations
                [1] 1Department of Molecular Cell Biology, Weizmann Institute of Science Rehovot, Israel
                Author notes

                Edited by: Hubert Vaudry, University of Rouen, France

                Reviewed by: Hubert Vaudry, University of Rouen, France; Atsuro Miyata, Kagoshima University, Japan

                *Correspondence: Gil Levkowitz, Department of Molecular Cell Biology, Weizmann Institute of Science, P. O. Box 26, Rehovot 76100, Israel. e-mail: gil.levkowitz@ 123456weizmann.ac.il

                This article was submitted to Frontiers in Neuroendocrine Science, a specialty of Frontiers in Endocrinology.

                Article
                DOI: 10.3389/fendo.2013.00055
                PMC ID: 3659299
                PubMed ID: 23734144
                SO-VID: 98e247e8-7700-438c-987a-2d0363ee188e
                Copyright © Copyright © 2013 Blechman and Levkowitz.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                Date received : 25 November 2012
                Date accepted : 24 April 2013
                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 187, Pages: 19, Words: 15482
                Categories
                Subject: Endocrinology
                Subject: Review Article

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: adcyap1r1,activity-dependent gene regulation,zebrafish model system,pacap receptor,stress disorders,post-traumatic,hypothalamic hormones,homeostasis
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: adcyap1r1, activity-dependent gene regulation, zebrafish model system, pacap receptor, stress disorders, post-traumatic, hypothalamic hormones, homeostasis

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