title: The mouse VPAC2 receptor confers suprachiasmatic nuclei cellular rhythmicity and responsiveness to vasoactive intestinal polypeptide in vitro.
abstract: Expression of coherent and rhythmic circadian (approximately 24 h) variation of behaviour, metabolism and other physiological processes in mammals is governed by a dominant biological clock located in the hypothalamic suprachiasmatic nuclei (SCN). Photic entrainment of the SCN circadian clock is mediated, in part, by vasoactive intestinal polypeptide (VIP) acting through the VPAC2 receptor. Here we used mice lacking the VPAC2 receptor (Vipr2-/-) to examine the contribution of this receptor to the electrophysiological actions of VIP on SCN neurons, and to the generation of SCN electrical firing rate rhythms SCN in vitro. Compared with wild-type controls, fewer SCN cells from Vipr2-/- mice responded to VIP and the VPAC2 receptor-selective agonist Ro 25-1553. By contrast, similar proportions of Vipr2-/- and wild-type SCN cells responded to gastrin-releasing peptide, arginine vasopressin or N-methyl-D-aspartate. Moreover, VIP-evoked responses from control SCN neurons were attenuated by the selective VPAC2 receptor antagonist PG 99-465. In firing rate rhythm experiments, the midday peak in activity observed in control SCN cells was lost in Vipr2-/- mice. The loss of electrical activity rhythm in Vipr2-/- mice was mimicked in control SCN slices by chronic treatment with PG 99-465. These results demonstrate that the VPAC2 receptor is necessary for the major part of the electrophysiological actions of VIP on SCN cells in vitro, and is of fundamental importance for the rhythmic and coherent expression of circadian rhythms governed by the SCN clock. These findings suggest a novel role of VPAC2 receptor signalling, and of cell-to-cell communication in general, in the maintenance of core clock function in mammals, impacting on the cellular physiology of SCN neurons.
authors.affiliation: School of Biological Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cutler
authors.forename: Mai
authors.initials: M
authors.lastname: Haraura
authors.forename: Helen E
authors.initials: HE
authors.lastname: Reed
authors.forename: Sanbing
authors.initials: S
authors.lastname: Shen
authors.forename: W John
authors.initials: WJ
authors.lastname: Sheward
authors.forename: Christine F
authors.initials: CF
authors.lastname: Morrison
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Marston
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Harmar
authors.forename: Hugh D
authors.initials: HD
authors.lastname: Piggins
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D002940:Circadian Rhythm / Q000502:physiology*; D004594:Electrophysiology; D019886:Gastrin-Releasing Peptide / Q000494:pharmacology; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D010456:Peptides, Cyclic / Q000494:pharmacology; D018005:Receptors, Vasoactive Intestinal Peptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D010456:Peptides, Cyclic; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; C089777:Ro 25-1553; D001127:Arginine Vasopressin; D014660:Vasoactive Intestinal Peptide; D016202:N-Methylaspartate; D019886:Gastrin-Releasing Peptide