Orexin-A activates hypothalamic AMP-activated protein kinase signaling through a Ca²âº-dependent mechanism involving voltage-gated L-type calcium channel.
Mol Pharmacol
; 84(6): 876-87, 2013 Dec.
Article
in En
| MEDLINE
| ID: mdl-24068427
ABSTRACT
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 Ca²âº 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-ß-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 Ca²âº-dependent mechanism involving the voltage-gated L-type calcium channel, which may serve as a potential target for regulating feeding behavior.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neuropeptides
/
Arcuate Nucleus of Hypothalamus
/
Calcium
/
Calcium Channels, L-Type
/
Intracellular Signaling Peptides and Proteins
/
AMP-Activated Protein Kinases
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Mol Pharmacol
Year:
2013
Document type:
Article