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Transcript
Pathways of insulin signaling. The binding of insulin to its plasma membrane receptor activates a cascade of downstream signaling events. Insulin binding activates the intrinsic tyrosine kinase activity of the receptor dimer, resulting in the tyrosine phosphorylation (Y-P) of the receptor's β subunits and a small number of specific substrates (yellow shapes): the Insulin Receptor Substrate (IRS) proteins, Gab-1 and SHC; within the membrane, a caveolar pool of insulin receptor phosphorylates caveolin (Cav), APS, and Cbl. These tyrosine-phosphorylated proteins interact with signaling cascades via SH2 and SH3 domains to mediate the effects of insulin, with specific effects resulting from each pathway. In target tissues such as skeletal muscle and adipocytes, a key event is the translocation of the Glut4 glucose transporter from intracellular vesicles to the plasma membrane; this translocation is stimulated by both the Source: Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia, Goodman & Gilman's: The Pharmacological Basis caveolar and non-caveolar pathways. In the non-caveolar pathway, the activation of PI3K is crucial, and PKB/Akt (anchored at the membrane by PIP3) of Therapeutics, 12e and/or an atypical form of PKC is involved. In the caveolar pathway, caveolar protein flotillin localizes the signaling complex to the caveola; the signaling Citation: Brunton LL,domain Chabnerinteractions BA, Knollmann BC. the Goodman Gilman's: Thethe Pharmacological Basis exchange of Therapeutics, 2011 at: pathway involves series of SH2 that add adaptor& protein CrkII, guanine nucleotide protein12e; C3G, andAvailable small GTPhttp://mhmedical.com/ Accessed: August 01, 2017 binding protein, TC10. The pathways are inactivated by specific phosphoprotein phosphatases (eg, PTB1B). In addition to the actions shown, insulin also Copyright 2017 McGraw-Hill Education. rights reserved stimulates the plasma ©membrane Na+,K+-ATPase by All a mechanism that is still being elucidated; the result is an increase in pump activity and a net