Corticotropin-releasing hormone (CRH) depresses n-methyl-D-aspartate receptor-mediated current in cultured rat hippocampal neurons via CRH receptor type 1.
CRH, the primary regulator of the neuroendocrine responses to stress, has been shown to modulate synaptic efficacy and the process of learning and memory in hippocampus. However, effects of CRH on N-methyl-d-aspartate (NMDA) receptor, the key receptor for synaptic plasticity, remain unclear. In primary cultured hippocampal neurons, using the technique of whole-cell patch-clamp recordings, we found that CRH (1 pmol/liter to 10 nmol/liter) inhibited NMDA-induced currents in a dose-dependent manner. This effect was reversed by the CRH receptor type 1 (CRHR1) antagonist antalarmin but not by the CRHR2 antagonist astressin-2B, suggesting that CRHR1 mediated the inhibitory effect of CRH. Investigations on the signaling pathways of CRH showed that CRH dose-dependently induced phosphorylated phospholipase C (PLC)-beta3 expression and increased intracellular cAMP content in these cells. Blocking PLC activity with U73122 prevented CRH-induced depression of NMDA current, whereas blocking protein kinase A (H89) and adenylate cyclase (SQ22536) failed to affect the CRH-induced depression of NMDA current. Application of inositol-1,4,5-triphosphate receptor (IP(3)R) antagonist, Ca(2+) chelators or protein kinase C (PKC) inhibitors also mainly blocked CRH-induced depression of NMDA currents, suggesting involvement of PLC/IP(3)R/Ca(2+)and PLC/PKC signaling pathways in CRH down-regulation of NMDA receptors. Our results suggest that CRH may exert neuromodulatory actions on hippocampus through regulating NMDA receptor function.
Sheng
Hui
H
Department of Physiology, Ministry of Education, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
Zhang
Yanmin
Y
Sun
Jihu
J
Gao
Lu
L
Ma
Bei
B
Lu
Jianqiang
J
Ni
Xin
X
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D054799:Phospholipase C beta / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000099052:CRF Receptor, Type 1
C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone; D016194:Receptors, N-Methyl-D-Aspartate; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054799:Phospholipase C beta; D000262:Adenylyl Cyclases