We investigated the effect of α-adrenergic and cholinergic receptor agonists on Ca2⁢ current in adult rat trigeminal ganglion neurons using whole-cell patch clamp methods. The application of acetylcholine, carbachol, and oxotremorine (50 ㄍM each) produced a rapid and reversible reduction of the Ca2⁢ current by 17⁑6%, 19⁑3%, and 18⁑4%, respectively. Atropine, a muscarinic antagonist, blocked carbachol- induced Ca2⁢ current inhibition to 3⁑1%. Norepinephrine (50 ㄍM) reduced Ca2⁢ current by 18⁑2%, while clonidine (50 ㄍM), an α2-adrenergic receptor agonist, inhibited Ca2⁢ current by only 4⁑1%. Yohimbine, an α2-adrenergic receptor antagonist, did not block the inhibitory effect of norepinephrine on Ca2⁢ current, whereas prazosin, an α1-adrenergic receptor antagonist, attenuated the inhibitory effect of norepinephrine on Ca2⁢ current to 6⁑1%. This pharmacology contrasts with α2-adrenergic receptor modulation of Ca2⁢ channels in rat sympathetic neurons, which is sensitive to clonidine and blocked by yohimbine. Our data suggest that the modulation of voltage dependent Ca2⁢ channel by norepinephrine is mediated via an α1-adrenergic receptor. Pretreatment with pertussis toxin (250 ng/ml) for 16 h greatly reduced norepinephrine- and carbachol-induced Ca2⁢ current inhibition from 17⁑3% and 18⁑3% to 2⁑1% and 2⁑1%, respectively. These results demonstrate that norepinephrine, through an α1-adrenergic receptor, and carbachol, through a muscarinic receptor, inhibit Ca2⁢ currents in adult rat trigeminal ganglion neurons via pertussis toxin sensitive GTP-binding proteins.