Carbon monoxide (CO) is produced constitutively in an oxygen-dependent manner by heme oxygenase enzymes and is increasingly being recognised as an important gas transmitter. It is of particular interest in the carotid body, where it has been shown both to decrease (Prabhakar et al., 1995) and to increase (Barbé et al., 2002) carotid sinus nerve (CSN) activity, in a manner that is sensitive to purinergic receptor antagonists. ATP is an important co-transmitter in carotid body chemotransduction, where it is released from glomus cells following hypercapnic or hypoxic stimulation. ATP then acts via P2X₂ and P2X₃ subunits found on petrosal neurons (Zhang et al., 2000). Here we use whole-cell voltage-clamp to show that CO exerts two different temporal responses on P2X₂ receptors expressed in HEK 293 cells. Data shown are mean ± s.e.m., p values are from Student’s t-test. Acute pre-application (5-10 s) of 30 µM CO donor (tricarbonyldichlororuthenium (II) dimer) caused a reversible sensitization of P2X receptors. The breakdown product of this CO donor was utilized as a control, and had no effect. Currents elicited by sub-maximal ATP (10 µM) were potentiated by 34.6 ± 7.2 % (n = 8). 30 µM CO did not increase the maximum ATP-evoked response, and did not significantly alter the EC₅₀ for ATP (control = 17.5 ± 2.2 µM; 30 µM CO = 15.6 ± 2.2 µM, n = 4, p > 0.1). However, 30 µM CO did significantly alter the Hill coefficient of the fitted concentration-response curves for each cell (control = 2.14 ± 0.4; 30 µM CO = 1.56 ± 0.1, n = 4, p < 0.05). This may suggest that CO alters the gating kinetics of the receptor, a hypothesis strengthened by the observation that CO also decreased the deactivation kinetics of the channel following removal of ATP (τ = 167 ± 13 ms for control; τ = 345 ± 16 ms for 30 µM CO, n = 4, p < 0.005). Both current potentiation and changes to deactivation kinetics were fully reversed following a 90 s wash. Chronic application (3-15 min) of 30 µM CO donor caused an inhibition of ATP-induced currents (9.6 ± 2.7 % current remaining after 15 min, n = 3). This inhibition appeared to be irreversible since there was no recovery following 6 min wash, though this may be due to accumulation of CO donor within the cell. The alteration in channel deactivation kinetics was maintained during chronic application of CO donor. Given the likely accumulation of the CO donor within the cell, these temporally distinct effects may represent two concentration dependent CO mechanisms of P2X₂ regulation. These observations may go some way to explain how CO may be both an activator and inhibitor of CNS activity, depending upon concentration.