Glucagon Receptor–Mediated Extracellular Signal–Regulated Kinase 1/2 Phosphorylation in Rat Mesangial Cells

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Abstract
Glucagon, a major insulin counterregulatory hormone, binds to specific G s protein–coupled receptors to activate glycogenolytic and gluconeogenic pathways, causing blood glucose levels to increase. Inappropriate increases in serum glucagon play a critical role in the development of insulin resistance and target organ damage in type 2 diabetes. We tested the hypotheses that: (1) glucagon induces proliferation of rat glomerular mesangial cells through glucagon receptor–activated phosphorylation of mitogen-activated protein kinase extracellular signal–regulated kinase 1/2 (p-ERK 1/2); and (2) this phosphorylation involves activation of cAMP-dependent protein kinase A (PKA) and phospholipase C (PLC)/[Ca 2+ ] i signaling pathways. In rat mesangial cells, glucagon (1 nM) stimulated [ 3 H]-thymidine incorporation by 96% ( P 1 -Glu 9 ] glucagon (1 μmol/L; P P P P P 1 -Glu 9 ] glucagon. Total ERK 1/2 was not affected by glucagon. Pretreating of mesangial cells with U73122 or H89 significantly attenuated ERK 1/2 phosphorylation induced by glucagon. We believe that these are the first data showing that glucagon activates specific receptors to induce ERK 1/2 phosphorylation and thereby increase mesangial cell proliferation and that this effect of glucagon involves both PLC/[Ca 2+ ] i - and cAMP-dependent PKA-activated signaling cascades.