title: Functional compensation between cholecystokinin-1 and -2 receptors in murine paraventricular nucleus neurons.
abstract: Cholecystokinin (CCK) and its receptor subtypes CCK-1 and -2 have diverse homeostatic functions. CCK-1 and -2 receptors share a common phosphatidylinositol signaling pathway, yet little is known regarding their possible functional coupling. We focused on CCK-mediated Ca(2+) signaling in parvocellular paraventricular nucleus (PVN) cells, which control satiety and other autonomic functions. Analysis of mouse hypothalamic slices demonstrated that the general CCK receptor agonist CCK-8s (10 nM) triggered Ca(2+) transients most significantly in the posterior subregion of the PVN (PaPo). This 10 nM CCK-8s-induced response was absent in CCK-1 receptor knock-out (CCK1R(-/-)) slices, showing that the response is mediated by CCK-1 receptors. CCK-8s concentrations higher than 30 nM triggered a Ca(2+) rise similarly in wild-type and CCK1R(-/-) slices. The large CCK-8s (100 nM)-induced Ca(2+) responses in CCK1R(-/-) slices were blocked by a CCK-2 receptor antagonist (CI-988), whereas those in wild-type slices required a mixture of CI-988 and lorglumide (a CCK-1 receptor antagonist) for complete antagonism. Therefore, CCK-1 and -2 receptors may function synergistically in single PaPo neurons and deletion of CCK-1 receptors may facilitate CCK-2 receptor signaling. This hypothesis was supported by results of real-time RT-PCR, immunofluorescence double labeling and Western blotting assays, which indicated CCK-2 receptor overexpression in PaPo neurons of CCK1R(-/-) mice. Furthermore, behavioral studies showed that intraperitoneal injections of lorglumide up-regulated food accesses in wild-type but not in CCK1R(-/-) mice, whereas CI-988 injections up-regulated food accesses in CCK1R(-/-) but not in wild-type mice. Compensatory CCK signaling via CCK-2 receptors in CCK1R(-/-) mice shed light on currently controversial satiety-controlling mechanisms.
authors.affiliation: Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama-city, Toyama 930-8555, Japan.
authors.forename: Shahid
authors.initials: S
authors.lastname: Mohammad
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ozaki
authors.forename: Kouhei
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Unno
authors.forename: Kurumi
authors.initials: K
authors.lastname: Yamoto
authors.forename: Eri
authors.initials: E
authors.lastname: Morioka
authors.forename: Soichi
authors.initials: S
authors.lastname: Takiguchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D019742:Chemokines, CC; D004305:Dose-Response Relationship, Drug; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018697:Nootropic Agents / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000378:metabolism*; D043887:Receptor, Cholecystokinin B / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011949:Receptors, Cholecystokinin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012844:Sincalide / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C090019:8-sulfocholecystokinin octapeptide; C511142:Ccl28 protein, mouse; D019742:Chemokines, CC; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D012844:Sincalide; D002118:Calcium