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Submitted on March 31, 2005
Accepted on September 20, 2005
Department of Endocrinology, Metabolism and Infectious Diseases, Hirosaki University School of Medicine, Hirosaki, Japan
* To whom correspondence should be addressed. E-mail: kkageyama{at}hkg.odn.ne.jp.
Hypothalamic corticotropin-releasing factor (CRF) stimulates synthesis and secretion of adrenocorticotropic hormone via CRF receptor type 1 (CRFR1) in the anterior pituitary gland. Following agonist-activated stimulation of receptor signaling, CRFR1 is down-regulated and desensitized. Generally, it is thought that G protein-coupled receptors may be desensitized by G protein-coupled receptor kinases (GRKs). However, the role of GRKs in corticotrophic cells has not been determined. In this study, we focused on involvement of GRKs in desensitization of CRFR1 by CRF in corticotrophic cells. We found that GRK2 (but not GRK3) mRNA and protein were expressed in rat anterior pituitary cells and AtT-20 cells (a line of mouse corticotroph tumor cells). To determine the role of GRK2 in CRF-induced desensitization of CRFR1 in mouse corticotrophs, AtT-20 cells were transfected with a dominant negative mutant GRK2 construct. CRF desensitized the cAMP-dependent response by CRFR1. Desensitization of CRFR1 by CRF was significantly less in AtT-20 cells transfected with the dominant negative mutant GRK2 construct compared with desensitization in control (an empty vector-transfected) AtT-20 cells. Furthermore, pre-treatment with a protein kinase A inhibitor also partially blocked desensitization of CRFR1 by CRF. These results suggest that GRK2 is involved in CRF-induced desensitization of CRFR1 in AtT-20 cells, and PKA pathway may also have an important role in desensitization of CRFR1by CRF seen in corticotrophic cells.
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