Calcitonin gene-related peptide (CGRP) is located with substance P in nerve varicosities in close apposition to principal neurons in airway parasympathetic ganglia. Substance P has multiple effects on airway parasympathetic neurons but the role of CGRP is unknown. Using intracellular current clamp recording of ganglionic neurons, stimulation of vagal afferent nerves in the presence of neurokinin receptor antagonists evoked hyperpolarization of the membrane potential which was blocked by the CGRP-1 receptor antagonist, CGRP(8-37). Exogenous application of alpha-CGRP (0.001-0.1 microM) hyperpolarized the membrane potential, which was either blocked or reversed to depolarization in the presence of CGRP(8-37), whereas higher concentrations of alpha-CGRP (1.0-10.0 microM) caused depolarization. Action potential accommodation in phasic-type neurons decreased in the presence of alpha-CGRP (0.1-10 microM). The co-localization of substance P- and CGRP-immunoreactivity was observed in nerve varicosities within ganglia; prolonged exposure to capsaicin in vitro depleted substance P and CGRP immunostaining in nerve varicosities. These results demonstrate that CGRP has multiple effects on the excitability of airway parasympathetic neurons and may alter their activity, ultimately affecting parasympathetic tone in the lower airways.