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Molecular Pharmacology

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Research ArticleArticle

Activation of Corticotropin-Releasing Factor Receptor 1 Selectively Inhibits CaV3.2 T-Type Calcium Channels

Jin Tao, Michael E. Hildebrand, Ping Liao, Mui Cheng Liang, Gregory Tan, Shengnan Li, Terrance P. Snutch and Tuck Wah Soong
Molecular Pharmacology June 2008, 73 (6) 1596-1609; DOI: https://doi.org/10.1124/mol.107.043612
Jin Tao
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Michael E. Hildebrand
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Ping Liao
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Mui Cheng Liang
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Gregory Tan
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Shengnan Li
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Terrance P. Snutch
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Tuck Wah Soong
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Abstract

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 CaV3.2 T-type calcium channels. Activation of CRFR1 by either CRF or urocortin (UCN) 1 reversibly inhibits CaV3.2 currents (IC50 of ∼30 nM), but it does not affect CaV3.1 or CaV3.3 channels. Blockade of CRFR1 by the antagonist astressin abolished the inhibition of CaV3.2 channels. The CRFR1-dependent inhibition of CaV3.2 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 βγ subunits (Gβγ). The inhibition of CaV3.2 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 CaV3.2 channels are widespread throughout the cardiovascular and nervous systems, the results point to a novel and functionally relevant CRFR1-CaV3.2 T-type calcium channel signaling pathway.

Footnotes

  • T.W.S. is supported by grants from the Biomedical Research Council, Singapore. T.P.S. is supported by an operating grant from the Canadian Institutes for Health Research and a Canada Research Chair.

  • ABBREVIATIONS: CRF, corticotropin-releasing factor; UCN, urocortin(s); CRFR, corticotropin-releasing factor receptor; GPCR, G protein-coupled receptor; HEK, human embryonic kidney; RGS, regulator of G protein signaling; MAS-GRK3, G protein-coupled receptor kinase; RT-PCR, reverse transcription-polymerase chain reaction; TBST, Tris-buffered saline/Tween 20; I-V, current-voltage; PTX, pertussis toxin; CTX, cholera toxin; GF-109203X, 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride; H-89, N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline; KN-93, 2-(N-[2-hydroxyethyl])-N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylamine; U-73122, 1-[6-[[17β-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione; PKA, cAMP-dependent protein kinase; Gβγ, G protein βγ subunit; GDPβS, guanosine-5′-O-(2-thiodiphosphate); GTPγS, guanosine-5′-O-(3-thiotriphosphate); PLC, phospholipase C; PKC, protein kinase C; TK, tyrosine kinase(s); ET-18-OCH3, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine; CaMKII, Ca2+/calmodulin-dependent protein kinase II; PI3K, phosphatidylinositol 3-kinase; RT, reverse transcriptase; PKI 5-24, protein kinase A inhibitor fragment 5-24.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received November 19, 2007.
    • Accepted February 21, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (6)
Molecular Pharmacology
Vol. 73, Issue 6
1 Jun 2008
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Research ArticleArticle

Activation of Corticotropin-Releasing Factor Receptor 1 Selectively Inhibits CaV3.2 T-Type Calcium Channels

Jin Tao, Michael E. Hildebrand, Ping Liao, Mui Cheng Liang, Gregory Tan, Shengnan Li, Terrance P. Snutch and Tuck Wah Soong
Molecular Pharmacology June 1, 2008, 73 (6) 1596-1609; DOI: https://doi.org/10.1124/mol.107.043612

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Research ArticleArticle

Activation of Corticotropin-Releasing Factor Receptor 1 Selectively Inhibits CaV3.2 T-Type Calcium Channels

Jin Tao, Michael E. Hildebrand, Ping Liao, Mui Cheng Liang, Gregory Tan, Shengnan Li, Terrance P. Snutch and Tuck Wah Soong
Molecular Pharmacology June 1, 2008, 73 (6) 1596-1609; DOI: https://doi.org/10.1124/mol.107.043612
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