title: Alternative splicing of the pituitary adenylate cyclase-activating polypetide (PACAP) receptor contributes to function of PACAP-27.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP)-27 and PACAP-38 are neuropeptides performing a variety of physiological functions. The PACAP-specific receptor PAC1 has several variants that result mainly from alternative splicing in the mRNA region encoding the first extracellular (EC1) domain and the third intracellular cytoplasmic (IC3) loop. To characterize the molecular forms of alternative splicing variants of PAC1, we examined the binding affinity and activation of two major second messenger pathways (cAMP production and changes in [Ca(2+)]( i )) by PACAP-27. Activation of cAMP was influenced by the variant in both of the EC1 domain and IC3 loops. In the N form in the EC1 domain, the suppressive effect of the HOP1 form in the IC3 loop was enhanced. Regarding the intracellular calcium mobilization assay, the rank order of the potency of PACAP-27 for the different PAC1 isoforms was S/HOP1>>N/R~S/R>>N/HOP1. In particular, PACAP-27 exhibited remarkable potency of calcium mobilization in the S/HOP1-expressing cells at sub-picomolar concentrations even though the affinities of PACAP-27 to the four PAC1 isoforms were not significantly different. This suggests the specific functions of PACAP-27 due to PACAP-27 preferring PAC1 activation, and leads in clarification of the pleiotoropic function of PACAP.
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Ushiyama
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ikeda
authors.forename: Morikatsu
authors.initials: M
authors.lastname: Yoshida
authors.forename: Kenji
authors.initials: K
authors.lastname: Mori
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Sugawara
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Inoue
authors.forename: Katsushi
authors.initials: K
authors.lastname: Yamada
authors.forename: Atsuro
authors.initials: A
authors.lastname: Miyata
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D051379:Mice; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism*; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D020033:Protein Isoforms; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D000242:Cyclic AMP; D002118:Calcium
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