Hypocretin-1 potentiates NMDA receptor-mediated somatodendritic secretion from locus ceruleus neurons.
Our previous observations showed that several stimuli, including high-K(+) solution, glutamate, and voltage pulses, induce somatic noradrenaline (NA) secretion from locus ceruleus (LC) neurons. Hypocretin (orexin), a hypothalamic peptide critical for normal wakefulness, has been shown to evoke NA release from the axon terminals of LC neurons. Here, we used amperometry to test the effect of hypocretin-1 (HCRT) on NMDA receptor-mediated somatodendritic release in LC neurons. Either HCRT or NMDA applied alone dose-dependently induced somatodendritic secretion. Bath application of HCRT notably potentiated NMDA receptor-mediated somatodendritic NA release. This potentiation was blocked by SB 334867, a selective HCRT receptor (Hcrtr 1) antagonist, or bisindolylmaleimide, a specific protein kinase C (PKC) inhibitor, indicating the involvement of Hcrtr 1 and PKC. Consistent with this, phorbol 12-myristate 13-acetate, a PKC activator, mimicked the HCRT-induced potentiation. Furthermore, HCRT enhanced NMDA-induced intracellular Ca(2+) elevation via activation of Hcrtr 1 and PKC, which may contribute to HCRT-potentiated somatodendritic secretion. These results suggest that HCRT modulates LC activity not only by regulating noradrenergic input to its targets, but also by affecting noradrenergic communication in the soma and dendrites.
Chen
Xiao-Wei
XW
Department of Physiology, Third Military Medical University, Chongqing 400038, China.
Mu
Yu
Y
Huang
Hong-Ping
HP
Guo
Ning
N
Zhang
Bo
B
Fan
Shuang-Yi
SY
Xiong
Jia-Xiang
JX
Wang
Shi-Rong
SR
Xiong
Wei
W
Huang
Wei
W
Liu
Tao
T
Zheng
Liang-Hong
LH
Zhang
Claire Xi
CX
Li
Li-Huan
LH
Yu
Zheng-Ping
ZP
Hu
Zhi-An
ZA
Zhou
Zhuan
Z
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000166:cytology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology*; D009479:Neuropeptides / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D000068797:Orexins; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D000068797:Orexins; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D002118:Calcium