S. Balasubramanian et Cs. Paulose, INDUCTION OF DNA-SYNTHESIS IN PRIMARY CULTURES OF RAT HEPATOCYTES BY SEROTONIN - POSSIBLE INVOLVEMENT OF SEROTONIN S-2 RECEPTOR, Hepatology, 27(1), 1998, pp. 62-66
The involvement of serotonin and its receptor subtype in the induction
of hepatocyte DNA synthesis was investigated in primary cultures of a
dult rat hepatocytes. Serotonin caused a dose-dependent increase in DN
A synthesis in primary cultures of rat hepatocytes in the presence of
epidermal growth factor (EGF) and insulin, as measured by [H-3]thymidi
ne incorporation. The serotonin S-2 receptor antagonists, ketanserin (
10(-6) mol/L) and spiperone (10(-6) mol/L), blocked stimulation of DNA
synthesis by serotonin. Displacement studies on [H-3]5-hydroxytryptam
ine (5-HT) binding to crude membranes from control and regenerating li
ver tissue, using cold ketanserin and spiperone, showed an increased i
nvolvement of S-2 receptors of serotonin in the regenerating liver dur
ing the DNA-synthetic phase. Serotonin enhanced the phosphorylation of
a 40-kd substrate protein of protein kinase C (PKC) in the regenerati
ng liver during the DNA synthetic phase of the hepatocyte cell cycle.
This was blocked by ketanserin, indicating that serotonin S-2 receptor
activates PKC, an important second messenger in cell growth and divis
ion, during rat liver regeneration. Our results show that serotonin ca
n act as a potent hepatocyte comitogen and induce DNA synthesis in pri
mary cultures of rat hepatocytes, which is suggested to be mediated th
rough the serotonin S-2 receptors of hepatocytes.