Representative intracellular g-protein coupled signal transduction cascades

Representative intracellular g-protein coupled signal transduction cascades. Subheading: Cell surface receptors, such as norepinephrine ß receptors, are coupled to stimulatory G (Gs) proteins. On transmitter binding, Gs activates adenylate cyclase (AC), catalyzing the formation of cyclic AMP from ATP ➀. Cyclic AMP is degraded to AMP by phosphodiesterases (PDE), which inactivate the cyclic AMP signal ➁. Cyclic AMP binds to the regulator subunits (R) of protein kinase A (PKA), resulting in a conformational change and the release of two catalytic subunits (C) ➂. The C subunits then are capable of phosphorylating serine and threonine residues on target polypeptides. One such protein is cyclic AMP response element binding protein (CREB), a transcriptional factor ➃. Phosphorylation of CREB results in translocation of CREB-P to the nucleus and subsequent binding to CRE-containing gene promoter regions activating expression ➄. A parallel pathway, exemplified by the 5-HT2A transductional cascade, couples to Gq (another stimulatory G protein), activating phospholipase C (PLC) catalyzing the conversion of phosphotidylinositol (PI) to diacylglycerol (DAG) and inositol triphosphate (IP3) ➅. IP3 mobilizes Ca2+ release from intracellular stores. DAG binds to protein kinase C resulting in phosphorylation of target proteins; these include both CREB and PKA ➆. The phosphorylation of PKA regulates the activity of the enzyme. Phosphorylated substrates are subsequently dephosphorylated by protein phosphatase 2A ➇. On dephosphorylation, CREB returns to the cytosol. Another regulator of PKA activity is protein kinase inhibitor (PKI); in the case of fibroblasts, this is the PKIγ isoform ➈. Both PKA and PKC can be glutathionylated, protecting them from oxidative degradation ➉. The activation loops of both enzymes are phosphorylated by phosphoinositide dependent kinase 1 (PDK1)

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The Molecular Neurobiology of Depression. () Richard C. Shelton. Psychiatr Clin North Am. ;30(1):1-11. Figure: F2. All organisms Homo sapiens Drosophila melanogaster

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