Forskolin but not cholera toxin bypasses flufenamate-induced inhibition of cAMP production in anterior pituitaries

Abstract

The pharmacological activators of adenylyl cyclase (cholera toxin and forskolin) were utilized in the present study to determine whether they could bypass the inhibitory effects of flufenamate on cAMP production in rat hemipituitaries. During 2 hr incubations, 10 microM flufenamate inhibited gonadotropin-releasing hormone (GnRH)-stimulated (25 nM) cAMP production. Flufenamate did not affect GnRH-receptor interactions as evidenced by its inability to significantly affect either the binding affinity or the binding capacity for GnRH. Additionally, flufenamate inhibited the cholera toxin-stimulated cAMP production, but was ineffective against forskolin-induced activation of adenylyl cyclase. These results indicate that forskolin can be used to restore cAMP production in the presence of flufenamate. Since GnRH and cholera toxin stimulate cAMP production via the GnRH receptor and the Gs protein respectively, and forskolin exerts its stimulatory effects via the catalytic component, the data are consistent with the possibility that flufenamate exerts its inhibitory effect at the level of the Gs protein.