Department of Physiology and Biophysics, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, United States.
Am J Physiol Lung Cell Mol Physiol. 2023 Mar 1;324(3):L259-L270. doi: 10.1152/ajplung.00099.2022. Epub 2023 Jan 24.
Severe levels of acidosis (pH < 6.8) have been shown to cause a sustained rise in cytosolic Ca concentration in carotid body Type 1 (glomus) cells. To understand how physiologically relevant levels of acidosis regulate Ca signaling in glomus cells, we studied the effects of small changes in extracellular pH (pH) on the kinetics of Ca oscillations. A decrease in pH from 7.4 to 7.3 (designated mild) and 7.2 (designated moderate) acidosis produced significant increases in the frequency and amplitude of Ca oscillations. These effects of acidosis on Ca 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 Ca oscillations was inhibited by nifedipine (1 µM; L-type Ca inhibitor) and by TTA-P2 (20 µM; T-type Ca inhibitor). Mild inhibition of TASK activity by -[(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-]pyrimidine-4-yl]-4-piperidinyl]-1-butanon (PK-THPP) (0.1 µM) increased Ca oscillation frequency to levels similar to those observed with mild-moderate acidosis. Mild acidosis (pH 7.3) and mild hypoxia (∼5%O) produced similar levels of changes in the kinetics of Ca oscillations. Block of tetraethylammonium (TEA)-sensitive K channels did not affect acid-induced increase in Ca oscillations. Our study shows that mild and moderate levels of acidosis increase the frequency and amplitude of Ca 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 pH.
严重的酸中毒（pH < 6.8）已被证明会导致颈动脉体 1 型（球）细胞胞质 Ca 浓度持续升高。为了了解生理相关水平的酸中毒如何调节球细胞中的 Ca 信号转导，我们研究了细胞外 pH（pH）小变化对 Ca 振荡动力学的影响。从 7.4 降至 7.3（轻度）和 7.2（中度）酸中毒使 Ca 振荡的频率和幅度显著增加。酸中毒对 Ca 振荡的这些影响不能被 NS383 和阿米洛利（酸感应离子通道（ASIC）抑制剂）阻断。然而，轻度和中度酸中毒会导致双孔域酸感应 K 通道（TASK）（TASK-1 和 TASK-3 样通道）的小但显著抑制，并使细胞去极化 6-13 mV。钙振荡的增加被硝苯地平（1 μM；L 型钙抑制剂）和 TTA-P2（20 μM；T 型钙抑制剂）抑制。通过-[[2,4-二氟苯基]甲基]-2'-[[[2-（4-甲氧基苯基）乙酰基]氨基]甲基][1,1'-联苯]-2-羧酰胺（A1899）（0.3 μM）和 1-[1-[6-[[1,1'-联苯]-4-基羰基）-5,6,7,8-四氢吡啶并[4,3-]嘧啶-4-基]-4-哌啶基]-1-丁酮（PK-THPP）（0.1 μM）轻度抑制 TASK 活性，将 Ca 振荡频率增加到与轻度中度酸中毒相似的水平。轻度酸中毒（pH 7.3）和轻度低氧（约 5%O）对 Ca 振荡动力学的变化产生相似的水平。四乙铵（TEA）敏感钾通道阻断不影响酸诱导的 Ca 振荡增加。我们的研究表明，轻度和中度酸中毒通过抑制 TASK 而不涉及 ASIC 来增加 Ca 振荡的频率和幅度，并且表明 TASK 在响应 pH 的生理变化的信号转导中起主要作用。
