Modulation of the heteromeric Kir4.1-Kir5.1 channels by PCO2 at physiological levels

Several inward rectifier K+ NO 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-CO2, 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-CO2,. 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 similar to5%) was seen with P-CO2 as low as 8 torr. Higher P-CO2 levels (23-60 torr) produced stronger inhibitions (by 30-40%). The inhibitions led to graded depolarizations (5-45 mV with P-CO2 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-CO2 levels. Such a modulation alters cellular excitability, and enables the cell to detect hypercapnia and hypocapnia in the presence of bicarbonate. (C) 2001 Wiley-Liss, Inc.