Induction of Inducible Nitric-oxide Synthase by the Heterotrimeric G Protein Gα₁₃*(∗)

While the functions of several G protein α subunits such as α_s and α_q are relatively well understood, the action of others such as α₁₃ remain largely undefined. Because of recent interest in regulation of nitric-oxide synthase (NOS) by G protein-coupled signaling systems and findings that receptors for two proinflammatory substances, thrombin and thromboxane couple to α₁₃, we studied the effect of α₁₃ on NOS activity in a renal epithelial cell line. We found that stable overexpression of α₁₃ or its GTPase-deficient mutant, α_13Q226L, in a continuous renal epithelial cell line (MCT) increased NOS activity. The increased NOS activity was due to increased expression of the macrophage-inducible form of NOS (iNOS). iNOS protein and activity were not increased in similar cells expressing an activated α_s (α_sQ227L) or were minimally increased in cells expressing activated α_i1 (α_i1Q204L) and α_q (α_qQ209L), members of the three other G protein α chain families. Transient co-expression of α₁₃ or α_13Q226L increased the activity of an iNOS promoter-CAT construct demonstrating that α₁₃ increases iNOS expression through transcription. Consequently, α₁₃ induces iNOS through a novel mechanism that is distinct from that of other G protein α chains and that may mediate the actions of G protein-dependent proinflammatory agents.