Neurotransmitter receptors mediate cyclic GMP formation by involvement of arachidonic acid and lipoxygenase

Evidence is presented that had led us to abandon the hypothesis that receptor-mediated cyclic GMP formation in cultured nerve cells occurs via the influx of extracellular calcium ions and an increase in the cytosolic free calcium ion concentration. While the cyclic GMP response is absolutely dependent on the presence of Ca²⁺, there is no increase in free intracellular Ca²⁺ subsequent to agonist stimulation. Instead, we have found that muscarinic or histamine H₁ receptor stimulation elicits the release of arachidonic acid through a quinacrine-sensitive mechanism, possibly phospholipase A₂. Inhibition of the release or metabolism of arachidonate by the lipoxygenase pathway prevents receptor-mediated cyclic GMP formation. We hypothesize that neurotransmitter receptors that mediate cyclic GMP synthesis function by releasing arachidonic acid and that an oxidative metabolite of arachidonic acid then stimulates soluble guanylate cyclase.