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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.

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*Department of Neurology, Medical Faculty, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany.
†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.
‡Harvard Medical School, Brigham and Women's Hospital and the VA Boston Healthcare System, Boston, MA, U.S.A.


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.

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