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.
Greenwood
A F
AF
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham 35294-0017.
Jope
R S
RS
D000818:Animals; D000911:Antibodies, Monoclonal; D001923:Brain Chemistry / Q000187:drug effects*; D002154:Calpain / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology; D015151:Immunoblotting; D066298:In Vitro Techniques; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical
D000911:Antibodies, Monoclonal; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D008094:Lithium; D002154:Calpain; D019204:GTP-Binding Proteins