Conditional, tissue-specific expression of Q205L Galphai2 in vivo mimics insulin activation of c-Jun N-terminal kinase and p38 kinase.
Deficiency of the G-protein subunit Galphai2 impairs insulin action (Moxham, C. M., and Malbon, C. C. (1996) Nature 379, 840-844). By using the promoter for the phosphoenolpyruvate carboxykinase gene, conditional, tissue-specific expression of the constitutively active mutant form (Q205L) of Galphai2 was achieved in mice harboring the transgene. Expression of Q205L Galphai2 was detected in skeletal muscle, liver, and adipose tissue of transgenic mice. Whereas the Galphai2-deficient mice displayed blunted insulin action, the Q205L Galphai2-expressing mice displayed enhanced insulin-like effects. Glycogen synthase in skeletal muscle was found to be activated in Q205L Galphai2-expressing mice, in the absence of the administration of insulin. Analysis of members of mitogen-activated protein kinase family revealed that both c-Jun N-terminal kinase and p38 are constitutively activated in vivo in the mice that express the Q205L Galphai2. ERK1,2, in contrast, are unaffected in the Q205L Galphai2-expressing mice. Insulin, like expression of Q205L Galphai2, activates both p38 and c-Jun N-terminal kinases as well as glycogen synthase. Activation of c-Jun N-terminal and p38 kinases in vivo with anisomycin, however, was insufficient to activate glycogen synthase. Much like Galphai2 deficiency provokes insulin resistance, expression of Q205L constitutively active Galphai2 mimics insulin action in vivo, sharing with insulin the activation of two mitogen-activated protein kinase members, p38 and c-Jun N-terminal kinases.
Guo
J H
JH
Department of Pharmacological Sciences, Diabetes and Metabolic Diseases Research Center, School of Medicine-HSC, State University of New York, Stony Brook, New York 11794-8651, USA.
Wang
H Y
HY
Malbon
C C
CC
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology; D006006:Glycogen Synthase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D007328:Insulin; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D000841:Anisomycin; D006006:Glycogen Synthase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse