title: An essential role for the K+-dependent Na+/Ca2+-exchanger, NCKX4, in melanocortin-4-receptor-dependent satiety.
abstract: K(+)-dependent Na(+)/Ca(2+)-exchangers are broadly expressed in various tissues, and particularly enriched in neurons of the brain. The distinct physiological roles for the different members of this Ca(2+) transporter family are, however, not well described. Here we show that gene-targeted mice lacking the K(+)-dependent Na(+)/Ca(2+)-exchanger, NCKX4 (gene slc24a4 or Nckx4), display a remarkable anorexia with severe hypophagia and weight loss. Feeding and satiety are coordinated centrally by melanocortin-4 receptors (MC4R) in neurons of the hypothalamic paraventricular nucleus (PVN). The hypophagic response of Nckx4 knock-out mice is accompanied by hyperactivation of neurons in the PVN, evidenced by high levels of c-Fos expression. The activation of PVN neurons in both fasted Nckx4 knock-out and glucose-injected wild-type animals is blocked by Ca(2+) removal and MC4R antagonists. In cultured hypothalamic neurons, melanocyte stimulating hormone induces an MC4R-dependent and sustained Ca(2+) signal, which requires phospholipase C activity and plasma membrane Ca(2+) entry. The Ca(2+) signal is enhanced in hypothalamic neurons from Nckx4 knock-out animals, and is depressed in cells in which NCKX4 is overexpressed. Finally, MC4R-dependent oxytocin expression in the PVN, a key essential step in satiety, is prevented by blocking phospholipase C activation or Ca(2+) entry. These findings highlight an essential, and to our knowledge previously unknown, role for Ca(2+) signaling in the MC4R pathway that leads to satiety, and a novel non-redundant role for NCKX4-mediated Ca(2+) extrusion in controlling MC4R signaling and feeding behavior. Together, these findings highlight a novel pathway that potentially could be exploited to develop much needed new therapeutics to tackle eating disorders and obesity.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Hotchkiss Brain Institute and Libin Cardiovascular Institute of Alberta, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4Z6, Canada.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Li
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Hotchkiss Brain Institute and Libin Cardiovascular Institute of Alberta, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4Z6, Canada jlytton@ucalgary.ca.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lytton
mesh_terms: D000818:Animals; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D005247:Feeding Behavior; D001068:Feeding and Eating Disorders / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010121:Oxytocin / Q000096:biosynthesis; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism* / Q000473:pathology; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism; D012528:Satiety Response
chemical_list: D017920:Antiporters; D044105:Receptor, Melanocortin, Type 4; C569957:Slc24a4 protein, mouse; D010121:Oxytocin
keywords: Calcium Signaling; Calcium Transport; Exchanger; Obesity; Sodium-Calcium Exchange
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