Orexin-A activates hypothalamic AMP-activated protein kinase signaling through a Ca²⁺-dependent mechanism involving voltage-gated L-type calcium channel.
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.
Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, Hubei, China (W.-N.W., P.-F.W., J.Z., X.-L.G., Z.Z., Y.-J.Y., L.-H.L., N.X., J.-G.C., F.W.); Key Laboratory of Neurologic Diseases (HUST), Ministry of Education of China, The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (P.-F.W., L.-H.L., N.X., J.-G.C., F.W.); and Department of Pharmacology, Anhui Medical University, Hefei, China (W.-N.W.).
Wen-Ning
WN
Wu
Peng-Fei
PF
Wu
Jun
J
Zhou
Xin-Lei
XL
Guan
Zui
Z
Zhang
Yuan-Jian
YJ
Yang
Li-Hong
LH
Long
Na
N
Xie
Jian-Guo
JG
Chen
Fang
F
Wang
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002478:Cells, Cultured; D005247:Feeding Behavior; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology*; D015640:Ion Channel Gating; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism; D000068797:Orexins; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
D020746:Calcium Channels, L-Type; C578627:Hcrtr1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D011493:Protein Kinase C; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D010738:Type C Phospholipases; D002118:Calcium