An Essential Role for the K+-Dependent Na+/Ca2+-Exchanger, NCKX4, in Melanocortin-4-Receptor-Dependent Satiety [Neurobiology]

August 5th, 2014 by Li, X.-F., Lytton, J.

K+-dependent Na+/Ca2+-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 Ca2+ transporter family are, however, not well described. Here we show that gene-targeted mice lacking the K+-dependent Na+/Ca2+-exchanger, nckx4 (slc24a4), 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 the nckx4 knock-out mice is accompanied by hyper-activation 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 Ca2+ removal and by MC4R antagonists. In cultured hypothalamic neurons, melanocyte stimulating hormone induces an MC4R-dependent and sustained Ca2+ signal, which requires phospholipase-C and plasma membrane Ca2+ entry. The Ca2+ 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 Ca2+ entry. These findings highlight an essential, and to our knowledge previously unknown, role for Ca2+-signaling in the MC4R pathway that leads to satiety, and a novel non-redundant role for NCKX4-mediated Ca2+ 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.