RT Journal Article SR Electronic T1 Orexin-A Activates Hypothalamic AMP-Activated Protein Kinase Signaling through a Ca2+-Dependent Mechanism Involving Voltage-Gated L-Type Calcium Channel JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 876 OP 887 DO 10.1124/mol.113.086744 VO 84 IS 6 A1 Wen-Ning Wu A1 Peng-Fei Wu A1 Jun Zhou A1 Xin-Lei Guan A1 Zui Zhang A1 Yuan-Jian Yang A1 Li-Hong Long A1 Na Xie A1 Jian-Guo Chen A1 Fang Wang YR 2013 UL http://molpharm.aspetjournals.org/content/84/6/876.abstract AB Hypothalamic AMP-activated protein kinase (AMPK) and orexins/hypocretins are both involved in the control of feeding behavior, but little is known about the interaction between these two signaling systems. Here, we demonstrated that orexin-A elicited significant activation of AMPK in the arcuate nucleus (ARC) of the hypothalamus by elevating cytosolic free Ca2+ involving extracellular calcium influx. Electrophysiological results revealed that orexin-A increased the L-type calcium current via the orexin receptor–phospholipase C–protein kinase C signaling pathway in ARC neurons that produce neuropeptide Y, an important downstream effector of orexin-A’s orexigenic effect. Furthermore, the L-type calcium channel inhibitor nifedipine attenuated orexin-A–induced AMPK activation in vitro and in vivo. We found that inhibition of AMPK by either compound C (6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-pyridinyl)-pyrazolo[1,5-a]pyrimidine) or the ATP-mimetic 9-β-D-arabinofuranoside prevented the appetite-stimulating effect of orexin-A. This action can be mimicked by nifedipine, the blocker of the L-type calcium channel. Our results indicated that orexin-A activates hypothalamic AMPK signaling through a Ca2+-dependent mechanism involving the voltage-gated L-type calcium channel, which may serve as a potential target for regulating feeding behavior.