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 [
acid-sensing ion channel (
ASIC) inhibitors]. Mild and moderate levels of
acidosis, however, caused a small but significant inhibition of two-pore domain
acid-sensing K+ channels (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 µM; L-type Cav inhibitor) and by
TTA-P2 (20 µM; T-type Cav inhibitor). Mild inhibition of TASK activity by N-[(2,4-difluorophenyl)methyl]-2'-[[[2-(4methoxyphenyl)acetyl]amino]methyl][1,1'-
biphenyl]-2-carboxamide (A1899) (0.3 µM) and 1-[1-[6-[[1,1'-
biphenyl]-4-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]
pyrimidine-4-yl]-4-piperidinyl]-1-butanon (PK-
THPP) (0.1 µM) increased Ca2+ oscillation frequency to levels similar to those observed with mild-moderate
acidosis. Mild
acidosis (pHo 7.3) and mild
hypoxia (∼5%O2) produced similar levels of changes in the kinetics of Ca2+ oscillations. Block of
tetraethylammonium (
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.