Regulation of insulin-stimulated tyrosine phosphorylation of Shc and IRS-1 in the muscle of rats: effect of growth hormone and epinephrine

Insulin receptor substrate-1 (IRS-1) and Shc protein have the same binding site at the insulin receptor and compete in their association with the phosphorylated receptor, The present study demonstrates that a decrease in the level of muscle insulin receptor phosphorylation induced by chronic growth hormone (GH) treatment or acute epinephrine infusion is accompanied by a reduction in the level of IRS-1 phosphorylation and in the association with phosphatidylinositol 3-kinase. In contrast, no change is observed in insulin-stimulated Shc tyrosine phosphorylation, or in the association of this substrate with Grb2. These data suggest that a reduction in insulin receptor phosphorylation may affect post-receptor processes differentially by preserving the phosphorylation of some substrates and pathways, but not of others. (C) 1998 Federation of European Biochemical Societies.421319119

Regulation of Platelet Function by Orai, STIM and TRP

Rosado J. (eds).Agonist-induced changes in cytosolic Ca2+ concentration ([Ca2+]c) are central events in platelet physiology. A major mechanism supporting agonist-induced Ca2+ signals is store-operated Ca2+ entry (SOCE), where the Ca2+ sensor STIM1 and the channels of the Orai family, as well as TRPC members are the key elements. STIM1-dependent SOCE plays a major role in collagen-stimulated Ca2+ signaling, phosphatidylserine exposure and thrombin generation. Furthermore, studies involving Orai1 gain-of-function mutants and platelets from Orai1-deficient mice have revealed the importance of this channel in thrombosis and hemostasis to those found in STIM1-deficient mice indicating that SOCE might play a prominent role in thrombus formation. Moreover, increase in TRPC6 expression might lead to thrombosis in humans. The role of STIM1, Orai1 and TRPCs, and thus SOCE, in thrombus formation, suggests that therapies directed against SOCE and targeting these molecules during cardiovascular and cerebrovascular events could significantly improve traditional anti-thrombotic treatments.This work was supported by MINECO (Grants BFU2013-45564-C2-1-P and BFU2013-45564-C2-2-P) and Junta de Extremadura-FEDER (GR15029). A. B-E is supported from UPF “MINECO – Plan Nacional de I+D+i(2008-2012) – SAF 2012-38140”.Peer reviewe

Second Messenger-Operated Calcium Entry Through TRPC6

International audienceCanonical transient receptor potential 6 (TRPC6) proteins assemble into heteromultimeric structures forming non-selective cation channels. In addition, many TRPC6-interacting proteins have been identified like some enzymes, channels, pumps, cytoskeleton-associated proteins, immunophilins, or cholesterol-binding proteins, indicating that TRPC6 are engaged into macromolecular complexes. Depending on the cell type and the experimental conditions used, TRPC6 activity has been reported to be controlled by diverse modalities. For instance, the second messenger diacylglycerol, store-depletion, the plant extract hyperforin or H2O2 have all been shown to trigger the opening of TRPC6 channels. A well-characterized consequence of TRPC6 activation is the elevation of the cytosolic concentration of Ca(2+). This latter response can reflect the entry of Ca(2+) through open TRPC6 channels but it can also be due to the Na(+)/Ca(2+) exchanger (operating in its reverse mode) or voltage-gated Ca(2+) channels (recruited in response to a TRPC6-mediated depolarization). Although TRPC6 controls a diverse array of biological functions in many tissues and cell types, its pathophysiological functions are far from being fully understood. This chapter covers some key features of TRPC6, with a special emphasis on their biological significance in kidney and blood cells