GRK3 mediates desensitization of CRF1 receptors: a potential mechanism regulating stress adaptation

GRK3 mediates desensitization of CRF1 receptors: a potential mechanism regulating stress adaptation Abstract Potential G protein-coupled receptor kinase (GRK) and protein kinase A (PKA) mediation of homologous desensitization of corticotropin-releasing factor type 1 (CRF 1 ) receptors was investigated in human retinoblastoma Y-79 cells. Inhibition of PKA activity by PKI 5–22 or H-89 failed to attenuate homologous desensitization of CRF 1 receptors, and direct activation of PKA by forskolin or dibutyryl cAMP failed to desensitize CRF-induced cAMP accumulation. However, treatment of permeabilized Y-79 cells with heparin, a nonselective GRK inhibitor, reduced homologous desensitization of CRF 1 receptors by ∼35%. Furthermore, Y-79 cell uptake of a GRK3 antisense oligonucleotide (ODN), but not of a random or mismatched ODN, reduced GRK3 mRNA expression by ∼50% without altering GRK2 mRNA expression and inhibited homologous desensitization of CRF 1 receptors by ∼55%. Finally, Y-79 cells transfected with a GRK3 antisense cDNA construct exhibited an ∼50% reduction in GRK3 protein expression and an ∼65% reduction in homologous desensitization of CRF 1 receptors. We conclude that GRK3 contributes importantly to the homologous desensitization of CRF 1 receptors in Y-79 cells, a brain-derived cell line. antisense G protein-coupled receptor kinase corticotropin-releasing factor type 1 receptor regulation homologous and heterologous desensitization of the CRF 1 receptor Footnotes R. L. Hauger received support from a Veterans Affairs Merit Review grant; the VA VISN 22 Mental Illness Research, Education and Clinical Center (MIRECC); and the National Institute of Mental Health Mental Health Clinical Research Center (PHS MH-20914–14). A portion of this research received financial support from the Max Planck Institute for Experimental Medicine, Department of Molecular Neuroendocrinology (Director: Dr. Joachim Spiess), Goettingen, Germany. Address for reprint requests and other correspondence: R. L. Hauger, VA Medical Center and Dept. of Psychiatry, Univ. of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603 (E-mail: rhauger@ucsd.edu ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Copyright © 2001 the American Physiological Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Regulatory, Integrative and Comparative Physiology The American Physiological Society

GRK3 mediates desensitization of CRF1 receptors: a potential mechanism regulating stress adaptation

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Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0363-6119
eISSN
1522-1490
Publisher site
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Abstract

Abstract Potential G protein-coupled receptor kinase (GRK) and protein kinase A (PKA) mediation of homologous desensitization of corticotropin-releasing factor type 1 (CRF 1 ) receptors was investigated in human retinoblastoma Y-79 cells. Inhibition of PKA activity by PKI 5–22 or H-89 failed to attenuate homologous desensitization of CRF 1 receptors, and direct activation of PKA by forskolin or dibutyryl cAMP failed to desensitize CRF-induced cAMP accumulation. However, treatment of permeabilized Y-79 cells with heparin, a nonselective GRK inhibitor, reduced homologous desensitization of CRF 1 receptors by ∼35%. Furthermore, Y-79 cell uptake of a GRK3 antisense oligonucleotide (ODN), but not of a random or mismatched ODN, reduced GRK3 mRNA expression by ∼50% without altering GRK2 mRNA expression and inhibited homologous desensitization of CRF 1 receptors by ∼55%. Finally, Y-79 cells transfected with a GRK3 antisense cDNA construct exhibited an ∼50% reduction in GRK3 protein expression and an ∼65% reduction in homologous desensitization of CRF 1 receptors. We conclude that GRK3 contributes importantly to the homologous desensitization of CRF 1 receptors in Y-79 cells, a brain-derived cell line. antisense G protein-coupled receptor kinase corticotropin-releasing factor type 1 receptor regulation homologous and heterologous desensitization of the CRF 1 receptor Footnotes R. L. Hauger received support from a Veterans Affairs Merit Review grant; the VA VISN 22 Mental Illness Research, Education and Clinical Center (MIRECC); and the National Institute of Mental Health Mental Health Clinical Research Center (PHS MH-20914–14). A portion of this research received financial support from the Max Planck Institute for Experimental Medicine, Department of Molecular Neuroendocrinology (Director: Dr. Joachim Spiess), Goettingen, Germany. Address for reprint requests and other correspondence: R. L. Hauger, VA Medical Center and Dept. of Psychiatry, Univ. of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603 (E-mail: rhauger@ucsd.edu ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Copyright © 2001 the American Physiological Society

Journal

AJP - Regulatory, Integrative and Comparative PhysiologyThe American Physiological Society

Published: Apr 1, 2001

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