The sodium-activated potassium channel Slack is modulated by hypercapnia and acidosis

Slack (Slo 2.2), a member of the Slo potassium channel family, is activated by both voltage and cytosolic factors, such as Na+ ([Na+]i) and Cl− ([Cl−]i). Since the Slo family is known to play a role in hypoxia, and since hypoxia/ischemia is associated with an increase in H+ and CO2 intracellularly, we hypothesized that the Slack channel may be affected by changes in intracellular concentrations of CO2 and H+. To examine this, we expressed the Slack channel in Xenopus oocytes and the Slo 2.2 protein was allowed to be inserted into the plasma membrane. Inside-out patch recordings were performed to examine the response of Slack to different CO2 concentrations (0.038%, 5%, 12%) and to different pH levels (6.3, 6.8, 7.3, 7.8, 8.3). In the presence of low [Na+]i (5 mM), the Slack channel open probability decreased when exposed to decreased pH or increased CO2 in a dose-dependent fashion (from 0.28±0.03, n=3, at pH 7.3 to 0.006±0.005, n=3, P=0.0004, at pH 6.8; and from 0.65±0.17, n=3, at 0.038% CO2 to 0.22±0.07, n=3, P=0.04 at 12% CO2). In the presence of high [Na+]i (45 mM), Slack open probability increased (from 0.03±0.01 at 5 mM [Na+]i, n=3, to 0.11±0.01, n=3, P=0.01) even in the presence of decreased pH (6.3). Since Slack activity increases significantly when exposed to increased [Na+]i, even in presence of increased H+, we propose that Slack may play an important role in pathological conditions during which there is an increase in the intracellular concentrations of both acid and Na+, such as in ischemia/hypoxia.