TASK inhibition by mild acidosis increases Ca2+ oscillations to mediate pH sensing in rat carotid body chemoreceptor cells

Am J Physiol Lung Cell Mol Physiol. 2023 Jan 24. doi: 10.1152/ajplung.00099.2022. Online ahead of print.

Abstract

Severe levels of acidosis (pH<6.8) have been shown to cause a sustained rise in cytosolic Ca2+ concentration in carotid body Type 1 (glomus) cells. To understand how physiologically relevant levels of acidosis regulate Ca2+ signaling in glomus cells, we studied the effects of small changes in extracellular pH (pHo) on the kinetics of Ca2+ oscillations. A decrease in pHo from 7.4 to 7.3 (designated mild) and 7.2 (designated moderate) acidosis produced significant increases in the frequency and amplitude of Ca2+ oscillations. These effects of acidosis on Ca2+ oscillations were not blocked by NS383 and amiloride (ASIC inhibitors). Mild and moderate levels of acidosis, however, caused a small but significant inhibition of TASK (TASK-1- and TASK-3- like channels) and depolarized the cell by 6-13 mV. Acidosis-induced increase in Ca2+ oscillations was inhibited by nifedipine (1 microM; L-type Cav inhibitor) and by TTA-P2 (20 microM; T-type Cav inhibitor). Mild inhibition of TASK activity by A1899 (0.3 microM) and PK-THPP (0.1 microM) increased Ca2+ oscillation frequency to levels similar to those observed with mild-moderate acidosis. Mild acidosis (pHo7.3 ) and mild hypoxia (~5%O2) produced similar level of changes in the kinetics of Ca2+ oscillations. Block of TEA-sensitive Kv channels did not affect acid-induced increase in Ca2+ oscillations. Our study shows that mild and moderate levels of acidosis increase the frequency and amplitude of Ca2+ oscillations primarily by inhibition of TASK without involving ASICs, and suggests a major role of TASK for signal transduction in response to a physiological change in pHo.

Keywords: Acidosis; Ca2+ oscillations; Carotid body; TASK.