NEUROPEPTIDE-Y Y-1 AND Y-2 RECEPTOR-MEDIATED STIMULATION OF MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVITY

Neuropeptide Y (NPY) regulates cardiovascular function, smooth muscle contraction and smooth muscle cell proliferation. Stimulation of NPY Y -1 and Y-2 receptor subtypes has been shown to result in increases in second messengers, such as cytosolic calcium concentrations, which pre cede physiological events such as cell contraction. To assess whether NPY receptors also stimulate second messengers which may precede mitog enic effects, we measured the mitogen-activated protein kinase (MAPK) activity in NPY receptor-expressing cell lines in response to NPY. CHO K1 cells stably expressing either NPY Y-1 or Y-2 receptors were shown to specifically bind radiolabelled Peptide YY (PYY), and MAPK activit y in these cells was assessed using a peptide kinase assay. NPY stimul ated dose-dependent increases in MAPK activity in both NPY Y-1 and Y-2 receptor-expressing cell lines. The NPY-stimulated MAPK activity was sensitive to pretreatment with pertussis toxin, the MAPK specific inhi bitor PD098059 or wortmannin, an inhibitor of phosphatidylinositol-3-k inase (PI-3-K). These results indicate that both NPY Y-1 and Y-2 recep tors stimulate wortmannin-sensitive increases in MAPK activity via G(i ) proteins and suggest a role for NPY Y-1 and Y-2 receptors in the reg ulation of smooth muscle cell growth involved in hypertrophy. (C) 1998 Elsevier Science B.V. All rights reserved.