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Biochem J. 2014 Aug 15;462(1):125-32. doi: 10.1042/BJ20131198.

Protein kinase inhibitor β enhances the constitutive activity of G-protein-coupled zinc receptor GPR39.

Author information

1
*Department of Neurology, Medical Faculty, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany.
2
†Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University Medical Center Mainz, Department of Neurology, Langenbeckstr. 1, D-55131 Mainz, Germany.
3
‡Harvard Medical School, Brigham and Women's Hospital and the VA Boston Healthcare System, Boston, MA, U.S.A.

Abstract

GPR39 is a G-protein-coupled zinc receptor that protects against diverse effectors of cell death. Its protective activity is mediated via constitutive activation of Gα13 and the RhoA pathway, leading to increased SRE (serum-response element)-dependent transcription; the zinc-dependent immediate activation of GPR39 involves Gq-mediated increases in cytosolic Ca2+ and Gs coupling leading to increased cAMP levels. We used the cytosolic and soluble C-terminus of GPR39 in a Y2H (yeast-2-hybrid) screen for interacting proteins, thus identifying PKIB (protein kinase A inhibitor β). Co-expression of GPR39 with PKIB increased the protective activity of GPR39 via the constitutive, but not the ligand-mediated, pathway. PKIB inhibits protein kinase A by direct interaction with its pseudosubstrate domain; mutation of this domain abolished the inhibitory activity of PKIB on protein kinase A activity, but had no effect on the interaction with GPR39, cell protection and induction of SRE-dependent transcription. Zinc caused dissociation of PKIB from GPR39, thereby liberating it to associate with protein kinase A and inhibit its activity, which would result in a negative-feedback loop with the ability to limit activation of the Gs pathway by zinc.

PMID:
24869658
DOI:
10.1042/BJ20131198
[Indexed for MEDLINE]

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