CONDITIONAL, TISSUE-SPECIFIC EXPRESSION OF Q205L G-ALPHA(I2) IN-VIVO MIMICS INSULIN ACTIVATION OF C-JUN N-TERMINAL KINASE AND P38 KINASE

Deficiency of the G-protein subunit G alpha(i2) impairs insulin action (Moxham, C, M,, and MaIbon, C, C, (1996) Nature 379, 840-844), By usi ng the promoter for the phosphoenolpyruvate carboxykinase gene, condit ional, tissue-specific expression of the constitutively active mutant form (Q205L) of G alpha(i2) was achieved in mice harboring the transge ne, Expression of Q205L Get, was detected in skeletal muscle, liver, a nd adipose tissue of transgenic mice. Whereas the G alpha(i2)-deficien t mice displayed blunted insulin action, the Q205L G alpha(i2)-express ing mice displayed enhanced insulin-like effects. Glycogen synthase in skeletal muscle was found to be activated in Q205L G alpha(i2)-expres sing mice, in the absence of the administration of insulin. Analysis o f members of mitogen-activated protein kinase family revealed that bot h c-Jun N-terminal kinase and p38 are constitutively activated in vivo in the mice that express the Q205L G alpha(i2) ERK1,2, in contrast, a re unaffected in the Q205L G alpha(i2)-expressing mice, Insulin, like expression of Q205L G alpha(i2), activates both p38 and c-Jun N-termin al kinases as well as glycogen synthase, Activation of c-Jun N-termina l and p38 kinases in vivo with anisomycin, however, was insufficient t o activate glycogen synthase, Much like G alpha(i2), deficiency provok es insulin resistance, expression of Q205L constitutively active G alp ha(i2) mimics insulin action in vivo, sharing with insulin the activat ion of two mitogen-activated protein kinase members, p38 and c-Jun N-t erminal kinases.