Faculty Collaboration Database

5-HT(2A) receptors stimulate mitogen-activated protein kinase via H(2)O(2) generation in rat renal mesangial cells. Am J Physiol Renal Physiol 2000 Apr;278(4):F650-8

Date

04/06/2000

Pubmed ID

10751227

DOI

10.1152/ajprenal.2000.278.4.F650

Scopus ID

2-s2.0-17544370809 (requires institutional sign-in at Scopus site)   83 Citations

Abstract

Serotonin (5-HT) stimulates mitogenesis in rat renal mesangial cells through a G protein-coupled 5-HT(2A) 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-HT(2A) 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., H(2)O(2) 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-HT(2A) receptor --> G(q) protein --> phospholipase C --> diacylglycerol --> classical PKC --> NAD(P)H oxidase --> superoxide --> superoxide dismutase --> H(2)O(2) --> mitogen-activated extracellular signal-regulated kinase --> ERK. These studies demonstrate a role for the 5-HT(2A) 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 H(2)O(2) 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.

Author List

Greene EL, Houghton O, Collinsworth G, Garnovskaya MN, Nagai T, Sajjad T, Bheemanathini V, Grewal JS, Paul RV, Raymond JR

Author

John R. Raymond MD President, CEO, Professor in the President department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cells, Cultured
Enzyme Activation
GTP-Binding Proteins
Glomerular Mesangium
Hydrogen Peroxide
Mitogen-Activated Protein Kinases
Phosphorylation
Protein Kinase C
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species
Receptor, Serotonin, 5-HT2A
Receptors, Serotonin
Serotonin
Type C Phospholipases
Virulence Factors, Bordetella