5-HYDROXYTRYPTAMINE(2A) RECEPTORS EXPRESSED IN RAT RENAL MESANGIAL CELLS INHIBIT CYCLIC-AMP ACCUMULATION

Second messenger coupling of the 5-hydroxytryptamine (5-HT)(2A) recept or endogenous to cultured rat glomerular mesangial cells was studied. 5-HT induced an increase in total inositol phosphate levels (EC(50) = 265 +/- 55 nM, maximum stimulation = 150 +/- 23%). That effect was sen sitive to antagonists of the 5-HT2A receptor and was insensitive to pe rtussis toxin at doses that eliminated detectable pertussis toxin subs trate, as determined by membrane ADP-ribosylation. Surprisingly, 5-HT also induced an inhibition of forskolin-stimulated cAMP accumulation ( 55 +/- 6%, IC50 = 5 +/- 3 nM). This effect was competitively antagoniz ed by the 5-HT2 receptor antagonists ketanserin, ritanserin, and spipe rone and could be produced by the 5-HT2 receptor agonists alpha-methyl -5-HT (66 +/- 13%, IC50 = 23 +/- 14 nM) and 1-(2,5-dimethoxy-4-iodophe nyl)-2-aminopropane (65 +/- 4%, IC50 = 14 +/- 7 nM). The inhibition of cAMP accumulation occurred in the presence of a number of agents that either stimulate or inhibit protein kinase C activity, arachidonic ac id metabolism, or Ca2+ mobilization. In isolated membranes, 5-HT induc ed a 36 +/- 5% inhibition of adenylyl cyclase activity (lC(50) = 8 +/- 4 nM). Inhibition of cAMP accumulation in intact cells and of adenyly l cyclase activity in washed membranes was (> 50%) sensitive to pertus sis toxin, implicating G(i alpha), or G(o alpha) subunits in the inhib itory signal. These data suggest that the 5-HT2A receptor can be permi ssive in its coupling to G proteins and second messengers.