Activation of corticotropin-releasing factor receptor 1 selectively inhibits CaV3.2 T-type calcium channels.
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(V)3.2 T-type calcium channels. Activation of CRFR1 by either CRF or urocortin (UCN) 1 reversibly inhibits Ca(V)3.2 currents (IC(50) of approximately 30 nM), but it does not affect Ca(V)3.1 or Ca(V)3.3 channels. Blockade of CRFR1 by the antagonist astressin abolished the inhibition of Ca(V)3.2 channels. The CRFR1-dependent inhibition of Ca(V)3.2 channels was independent of the activities of phospholipase C, tyrosine kinases, Ca(2+)/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 betagamma subunits (Gbetagamma). The inhibition of Ca(V)3.2 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(V)3.2 channels are widespread throughout the cardiovascular and nervous systems, the results point to a novel and functionally relevant CRFR1-Ca(V)3.2 T-type calcium channel signaling pathway.
Tao
Jin
J
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
Hildebrand
Michael E
ME
Liao
Ping
P
Liang
Mui Cheng
MC
Tan
Gregory
G
Li
Shengnan
S
Snutch
Terrance P
TP
Soong
Tuck Wah
TW
D000818:Animals; D002121:Calcium Channel Blockers / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D051379:Mice; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D054832:Urocortins / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
C479952:CACNA1H protein, human; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D000099052:CRF Receptor, Type 1