Brain G-protein proteolysis by calpain: enhancement by lithium

Heterotrimeric G-proteins mediate many receptor-coupled signal transduction processes and the cellular concentrations of G-proteins are modulated by several factors, including development, activity, and drugs. The mechanisms causing changes in G-protein concentrations are mostly unknown. The purpose of this study was to determine if G-proteins could be proteolyzed by calpain, a calcium-activated neutral protease that has been linked with neuronal plasticity. In membranes prepared from rat cerebral cortex, calpain rapidly cleaved the alpha-subunit of Go but did not hydrolyze beta-subunits. Comparisons of the proteolysis of different alpha-subunits revealed that they were differentially susceptible to calpain-induced proteolysis in the order of alpha s > alpha o > alpha q > alpha i. Preincubation of cortical membranes with GTP gamma S, which binds to G alpha and causes its dissociation from the beta gamma dimer, reduced calpain-mediated proteolysis of alpha o. Lithium, the primary treatment for mania, enhanced the calpain-mediated proteolysis of alpha o in the heterotrimeric state but did not affect proteolysis of dissociated, GTP gamma S-bound alpha o. These results demonstrate that proteolysis by calpain is a potential mechanism by which cellular G-protein concentrations can be regulated.