Regulation of Ca2+-sensitive adenylyl cyclase in gonadotropin-releasing hormone neurons

In immortalized GnRH neurons, cAMP production is elevated by increased extr acellular Ca2+ and the Ca2+ channel agonist, BK-8644, and is diminished by low extracellular Ca2+ and treatment with nifedipine, consistent with the e xpression of adenylyl cyclase type I (AC I). Potassium-induced depolarizati on of GT1-7 neurons causes a dose-dependent monotonic increase in [Ca2+](i) and elicits a bell-shaped cAMP response. The inhibitory phase of the cAMP response is prevented by pertussis toxin (PTX), consistent with the activat ion of G(i)-related proteins during depolarization. Agonist activation of t he endogenous GnRH receptor in GT1-7 neurons also elicits a bell-shaped cha nge in cAMP production. The inhibitory action of high GnRH concentrations i s prevented by PTX, indicating coupling of the GnRH receptors to G(i)-relat ed proteins. The stimulation of cAMP production by activation of endogenous LH receptors is enhanced by low (nanomolar) concentrations of GnRH but is abolished by micromolar concentrations of GnRH, again in a PTX-sensitive ma nner. These findings indicate that GnRH neuronal cAMP production is maintai ned by Ca2+ entry through voltage-sensitive calcium channels, leading to ac tivation of Ca2+-stimulated AC I. Furthermore, the Ca2+ influx-dependent ac tivation of AC I acts in conjunction with AC-regulatory G proteins to deter mine basal and agonist-stimulated levels of cAMP production.