FIG. 8.

Interaction of GPCR, Ca²⁺, RTK, and small GTPase signaling affecting redox gene expression. (A) GPCR Gα and Gβγ activation increases signaling through cAMP, PLC, small GTPases, PI3K-AKT, RAS, and RAF, which are among the redox-linked signal transduction molecules, thereby stimulating expression of SOD1–3 and NADPH oxidases NOX1, −2, −4, and −5. RTK activation occurs at the level of RAF and PI3K signaling molecules. (B) Ca²⁺ increases small GTPase RHO-ROCK signaling that stimulates NOX5 expression. Ca²⁺ activates also PKC-ERK1/2 pathway causing increased SOD2 and SOD3 production. (C) RTK and small GTPase activation stimulate ERK1/2 signal transduction that promotes SOD3 expression and formation of a regulatory loop affecting small GTPase activation. Mutant SOD1 binds to small GPTase RAC in a redox-insensitive manner causing continuous ROS production and inflammatory cytokine synthesis.