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Am J Physiol Renal Physiol 278: F650-F658, 2000;
0363-6127/00 $5.00
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Vol. 278, Issue 4, F650-F658, April 2000

5-HT2A receptors stimulate mitogen-activated protein kinase via H2O2 generation in rat renal mesangial cells

Eddie L. Greene, Odette Houghton, Georgiann Collinsworth, Maria N. Garnovskaya, Toshio Nagai, Tahir Sajjad, Venugopala Bheemanathini, Jasjit S. Grewal, Richard V. Paul, and John R. Raymond

Nephrology Division, Department of Internal Medicine, Medical University of South Carolina, and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29425

Serotonin (5-HT) stimulates mitogenesis in rat renal mesangial cells through a G protein-coupled 5-HT2A receptor. We tested the hypothesis that oxidants might be involved in the signal transduction pathway linking the receptor to extracellular signal-regulated protein kinase (ERK). 5-HT rapidly increased the activity and phosphorylation of ERK. These effects were blocked by the 5-HT2A receptor antagonist ketanserin. The peak effect was noted at 5-10 min, and half-maximal stimulation was achieved at 10-30 nM 5-HT. Chemical inhibitor and activator studies supported the involvement of phospholipase C, protein kinase C (PKC), and reactive oxygen species (ROS, i.e., H2O2 and superoxide) generated by an NAD(P)H oxidase-like enzyme in the ERK activation cascade. Mapping studies supported a location for the NAD(P)H oxidase enzyme and the ROS downstream from PKC. Our studies are most consistent with an ERK activation pathway as follows: 5-HT2A receptor right-arrow Gq protein right-arrow phospholipase C right-arrow diacylglycerol right-arrow classical PKC right-arrow NAD(P)H oxidase right-arrow superoxide right-arrow superoxide dismutase right-arrow H2O2 right-arrow mitogen-activated extracellular signal-regulated kinase right-arrow ERK. These studies demonstrate a role for the 5-HT2A receptor in rapid, potent, and efficacious activation of ERK in rat renal mesangial cells. They support a role for oxidants in conveying the stimulatory signal from 5-HT, because 1) chemical antioxidants attenuate the 5-HT signal, 2) oxidants and 5-HT selectively activate ERK to a similar degree, 3) 5-HT produces superoxide and H2O2 in these cells, and 4) a specific enzyme [NAD(P)H oxidase] has been implicated as the source of the ROS, which react selectively downstream of classical PKC.

serotonin receptor; kidney; signal transduction; reactive oxygen species; NADP(H) oxidase


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