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Activation of Corticotropin-Releasing Factor Receptor 1 Selectively Inhibits Ca_V3.2 T-Type Calcium Channels

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (J.T., P.L., M.C.L., G.T., T.W.S.); Michael Smith Laboratories, University of British Columbia, Vancouver, Canada (M.E.H., T.P.S.); Department of Pharmacology, Nanjing Medical University, Nanjing, China (J.T., S.L.); and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (T.W.S.)

The corticotropin-releasing factor (CRF) peptides CRF and uro-cortins 1 to 3 are crucial regulators of mammalian stress and inflammatory responses, and they are also implicated in disorders such as anxiety, depression, and drug addiction. There is considerable interest in the physiological mechanisms by which CRF receptors mediate their widespread effects, and here we report that the native CRF receptor 1 (CRFR1) endogenous to the human embryonic kidney 293 cells can functionally couple to mammalian Ca_V3.2 T-type calcium channels. Activation of CRFR1 by either CRF or urocortin (UCN) 1 reversibly inhibits Ca_V3.2 currents (IC₅₀ of 30 nM), but it does not affect Ca_V3.1 or Ca_V3.3 channels. Blockade of CRFR1 by the antagonist astressin abolished the inhibition of Ca_V3.2 channels. The CRFR1-dependent inhibition of Ca_V3.2 channels was independent of the activities of phospholipase C, tyrosine kinases, Ca²⁺/calmodulin-dependent protein kinase II, protein kinase C, and other kinase pathways, but it was dependent upon a cholera toxin-sensitive G protein-mediated mechanism relying upon G protein β subunits (Gβ). The inhibition of Ca_V3.2 channels via the activation of CRFR1 was due to a hyperpolarized shift in their steady-state inactivation, and it was reversible upon washout of the agonists. Given that UCN affect multiple aspects of cardiac and neuronal physiology and that Ca_V3.2 channels are widespread throughout the cardiovascular and nervous systems, the results point to a novel and functionally relevant CRFR1-Ca_V3.2 T-type calcium channel signaling pathway.

Address correspondence to: Dr. Tuck Wah Soong, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597. E-mail: phsstw{at}nus.edu.sg

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Making the T-Type Even Tinier: Corticotropin-Releasing Factor-Mediated Inhibition of Low-Voltage-Activated Calcium Channel Activity

Diego L. Varela, Tamara Hermosilla, and Gerald W. Zamponi
MolPharm 2008 73: 1589-1591. [Abstract] [Full Text]  

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