Modulation of Ca2+ channels by neurotransmitters provides critical control of neuronal excitability and synaptic strength. Little is known about regulation of the Ca2+ efflux pathways that counterbalance Ca2+ influx in neurons. We demonstrate that bradykinin and ATP significantly facilitate removal of action potential-induced Ca2+ loads by stimulating plasma membrane Ca2+-ATPases (PMCAs) in rat sensory neurons. This effect was mimicked in the soma and axonal varicosities by phorbol esters and was blocked by antagonists of protein kinase C (PKC). Reduced expression of PMCA isoform 4 abolished, and overexpression of isoform 4b enhanced, PKC-dependent facilitation of Ca2+ efflux. This acceleration of PMCA4 underlies the shortening of the action potential afterhyperpolarization produced by activation of bradykinin and purinergic receptors. Thus, isoform-specific modulation of PMCA-mediated Ca2+ efflux represents a novel mechanism to control excitability in sensory neurons.