MECHANISM OF STIMULATION OF CYCLIC-GMP LEVEL IN A NEURONAL CELL-LINE MEDIATED BY SEROTONIN (5-HT3) RECEPTORS - INVOLVEMENT OF NITRIC-OXIDE, ARACHIDONIC-ACID METABOLISM AND CYTOSOLIC CA-2+

The mechanism by which serotonin (5‐HT3) receptors mediate a rise in cyclic‐GMP level was investigated in a neuronal cell line. Inhibitors of phospholipase A2 (mepacrine) and of lipoxygenase (eicosatetraynoic acid or nordihydroguaiaretic acid) suppressed the action of serotonin. On the other hand, inhibition by hemoglobin indicates a role for nitric oxide which could be in part responsible for the cyclic‐GMP effect as an intercellular stimulant. The suppression of the serotonin effect by the arginine analogues Nω‐methyl‐L‐arginine and canavanine is consistent with the notion that nitric oxide could be released from arginine. The serotonin‐induced rise of cyclic‐GMP level depends on the presence of extracellular Ca2+ with half‐maximal stimulation at 0.3 mM Ca2+. The serotonin‐stimulated rise of cyclic GMP was inhibited by (a) addition of inorganic blockers of Ca2+‐permeable channels (La3+, half‐maximal inhibitory concentration (IC50) 0.04 mM; Mn2+, IC50, 0.4 mM; Co2+, IC50, 0.9 mM; Ni2+, IC50, 1.2 mM) and (b) of organic blockers (diltiazem: IC50, 6 μM, methoxyverapamil: IC50, 3 μM and (c) intracellular application of the Ca2+ chelator bis‐(O‐aminophenoxy)‐ethane‐N,N,N′,N′‐tetraacetic acid (IC50, 2 μM). Thus, two pathways for the activation of soluble guanylate cyclase by serotonin are possible: (a) via lipoxygenase products of arachidonic acid and/or (b) via nitric oxide or a related nitroso compound. Serotonin mediates a rise of cytosolic Ca2+ activity due to entry of extracellular Ca2+. It still has to be investigated which step depends on a rise of cytosolic Ca2+ activity that appears to be a prerequisite for activation of guanylate cyclase. Copyright © 1990, Wiley Blackwell. All rights reserved