Serotonin stimulates DNA synthesis in fibroblasts acting through 5–HT_1B receptors coupled to a G_i-protein

Abstract

Growth factors can be divided into two classes which act through distinct signal transduction pathways¹. One class including epidermal growth factor, platelet derived growth factor and fibroblast growth factor activates receptor tyrosine kinases^2,3, and the second class, including thrombin^4,5, bombesin^6,7, bradykinin⁷ and vasopressin^7,8 activates a phosphoinositide-specific phospholipase C through GTP-binding proteins⁹ which can be inactivated by pertussis toxin¹⁰. In Chinese hamster lung fibroblasts, thrombin-induced mitogenicity seems to correlate well with phospholipase C activation and both events are sensitive to pertussis toxin^1,5,11. Thrombin^12,13, like the other mitogens in this class^14–16, simultaneously inhibits adenylate cyclase. This involves an inhibitory G protein (G_i), a well established pertussis toxin substrate^17,18. The relative contributions of the two signalling pathways to mitogenicity has not been evaluated so far. We report here that the neurotransmitter serotonin (5-hydroxytryptamine), a contracting agent¹⁹ and mitogen for smooth muscle cells²⁰, activates phospholipase C, inhibits adenylate cyclase and stimulates DNA synthesis in fibroblasts. These events are sensitive to pertussis toxin. We show that the mitogenicity of 5-hydroxytryptamine can be uncoupled from phospholipase C activation that is mediated by 5-HT₂ receptors, but correlates perfectly with inhibition of adenylate cyclase through 5-HT_1B receptors. We propose that inhibition of adenylate cyclase or activation of an undefined effector system by G_i is important in 5-hydroxytryptamine induced DNA synthesis and contributes to the strong mitogenicity of the other members of this family of growth factors.