title: Cytosolic Ca2+ responses to sub-picomolar and nanomolar PACAP in pancreatic beta-cells are mediated by VPAC2 and PAC1 receptors.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) potentiates glucose-induced insulin release and increases cytosolic Ca2+ concentration ([Ca2+]i) in islet beta-cells in a concentration-dependent manner with two peaks at 10(-13) and 10(-9) M. PAC1 receptor (PAC1-R) and VPAC2 receptor (VPAC2-R) are expressed in pancreatic beta-cells and thought to be involved in insulin release. We aimed to determine the receptor types involved in the [Ca2+]i responses to 10(-13) and 10(-9) M PACAP. We measured [Ca2+]i in beta-cells and examined comparative effects of PAC1-R-selective agonist maxadilan, its antagonist M65, VPAC2-R-selective agonist Ro25-1553, and native ligands of PACAP and VIP. In the presence of 8.3 mM glucose, maxadilan, Ro25-1553, PACAP, and VIP at 10(-13) and 10(-9) M all increased [Ca2+]i. PACAP and maxadilan elicited greater effects at 10(-9) M than at 10(-13) M both in the incidence and amplitude of [Ca2+]i responses. For VIP and Ro25-1553, in contrast, the effects at 10(-9) and 10(-13) M were comparable. Furthermore, the amplitude of [Ca2+]i responses to 10(-9) M PACAP, but not 10(-13) M PACAP, was suppressed by M65. The results suggest that VPAC2-R and PAC1-R contribute equally to [Ca2+]i responses to sub-picomolar concentrations of PACAP, while PAC1-R has greater contribution to [Ca2+]i responses to nanomolar concentrations of this peptide.
authors.affiliation: Division of Integrative Physiology, Department of Physiology, School of Medicine, Jichi Medical School, Minamikawachi, Kawachi, Tochigi 329-0498, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Watanabe
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000008:administration & dosage*; D009479:Neuropeptides / Q000008:administration & dosage*; D018377:Neurotransmitter Agents / Q000008:administration & dosage*; D010456:Peptides, Cyclic / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism*; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D018005:Receptors, Vasoactive Intestinal Peptide / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C495403:Adcyap1 protein, rat; C495505:Adcyap1r1 protein, rat; D007328:Insulin; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D010456:Peptides, Cyclic; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011956:Receptors, Cell Surface; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; C089777:Ro 25-1553; C495511:Vipr2 protein, rat; D014660:Vasoactive Intestinal Peptide; D002118:Calcium