Activation of corticotropin-releasing factor 2 receptor inhibits Purkinje neuron P-type calcium currents via G(o)alpha-dependent PKC epsilon pathway.
Corticotropin-releasing factor (CRF) receptors have been demonstrated to be widely expressed in the central nervous system and in many peripheral tissues of mammalians. However, it is still unknown whether CRF receptors will function in cerebellar Purkinje neurons. In the present study, we investigated the expression profile of CRF receptors in rat cerebellum and identified a novel functional role of CRFR2 in modulating Purkinje neuron P-type Ca(2+) currents (P-currents). We found that CRFR2alpha mRNA, but not CRFR1 and CRFR2beta, was endogenously expressed in rat cerebellum. Activation of CRFR2 by UCN2 inhibited P-currents in a concentration-dependent manner (IC(50) approximately 0.07 microM). This inhibitory effect was abolished by astressin2B, a CRFR2 antagonist, and was blocked by GDP-beta-S, pertussis toxin, or a selective antibody raised against the G(o)alpha. Inhibition of phospholipase C (PLC) blocked the inhibitory action of UCN2. The application of diacylglycerol (DAG) antagonist, 1-hexadecyl-2-acetyl-sn-glycerol, as well as inhibition of either protein kinase C or its epsilon isoform (PKCepsilon) abolished the UCN2 effect while 1-oleoyl-2-acetyl-sn-glycerol (EI-150), a membrane-permeable DAG analogue, occluded UCN2-mediated inhibition. In addition, UCN2 significantly increases spontaneous firing frequency of Purkinje neurons in cerebellar slices. In summary, activation of CRFR2 inhibits P-currents in Purkinje neurons via G(o)alpha-dependent PLC/PKCepsilon pathway, which might contribute to its physiological functions in the cerebellum.
Department of Neurobiology, Laboratory of Aging and Nervous Diseases, Medical College of Soochow University, Suzhou, PR China. taoj@suda.edu.cn
Jin
J
Tao
Yuan
Y
Zhang
Hua
H
Huang
Xinghong
X
Jiang
D000818:Animals; D020865:Calcium Channels, P-Type / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology; D004075:Diglycerides / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D005995:Glyceryl Ethers / Q000494:pharmacology; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D011689:Purkinje Cells / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
C101531:CRF receptor type 2; D020865:Calcium Channels, P-Type; D004075:Diglycerides; D005995:Glyceryl Ethers; D018019:Receptors, Corticotropin-Releasing Hormone; C038237:1-oleoyl-2-acetylglycerol; D003346:Corticotropin-Releasing Hormone; C055394:1-palmityl-2-acetylglycerol; D051744:Protein Kinase C-epsilon; D010738:Type C Phospholipases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go