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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 
Gq protein phospholipase C diacylglycerol
classical PKC NAD(P)H oxidase superoxide superoxide dismutase H2O2 mitogen-activated extracellular
signal-regulated kinase 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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