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

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 Ga13 and the RhoA pathway, leading to increased serum response element (SRE)-dependent transcription; the zinc-dependent immediate activation of GPR39 involves Gq-mediated increases in cytosolic Ca2+ and Gs coupling leading to increased cyclic AMP levels. We used the cytosolic and soluble C-terminus of GPR39 in a yeast-2-hybrid screen for interacting proteins, thus identifying the protein kinase A inhibitor beta (PKIB). 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.

Source: BJ Cell - May 28, 2014 Category: Biochemistry Authors: Z Kovacs, T Schacht, A Herrmann, P Albrecht, K Lefkimmiatis, A Methner Tags: BJ Signal Source Type: research