AbstractSeveral inward rectifier K+ (Kir) channels are pH‐sensitive, making them potential candidates for CO2 chemoreception in cells. However, there is no evidence showing that Kir channels change their activity at near physiological level of P, as most previous studies were done using high concentrations of CO2. It is known that the heteromeric Kir4.1–Kir5.1 channels are highly sensitive to intracellular protons with pKa value right at the physiological pH level. Such a pKa value may allow these channels to regulate membrane potentials with modest changes in P. To test this hypothesis, we studied the Kir4.1–Kir5.1 currents expressed in Xenopus oocytes and membrane potentials in the presence and absence of bicarbonate. Evident inhibition of these currents (by ∼5%) was seen with P as low as 8 torr. Higher P levels (23–60 torr) produced stronger inhibitions (by 30–40%). The inhibitions led to graded depolarizations (5–45 mV with P 8–60 torr). Similar effects were observed in the presence of 24 mM bicarbonate and 5% CO2. Indeed, the Kir4.1–Kir5.1 currents were enhanced with 3% CO2 and suppressed with 8% CO2 in voltage clamp, resulting in hyper‐ (−9 mV) and depolarization (16 mV) in current clamp, respectively. With physiological concentration of extracellular K+, the Kir4.1–Kir5.1 channels conduct substantial outward currents that were similarly inhibited by CO2 as their inward rectifying currents. These results therefore indicate that the heteromeric Kir4.1–Kir5.1 channels are modulated by a modest change in P levels. Such a modulation alters cellular excitability, and enables the cell to detect hypercapnia and hypocapnia in the presence of bicarbonate. © 2001 Wiley‐Liss, Inc.