Acidic extracellular pH-activated outwardly rectifying chloride current in mammalian cardiac myocytes

Abstract

Yamamoto, Shintaro, and Tsuguhisa Ehara. Acidic extracellular pH-activated outwardly rectifying chloride current in mammalian cardiac myocytes. Am J Physiol Heart Circ Physiol 290: H1905-H1914, 2006. First published December 9, 2005 doi:10.1152/ajpheart.00965.2005.-Extracellular acidic pH was found to induce an outwardly rectifying Cl Ϫ current (ICl,acid) in mouse ventricular cells, with a half-maximal activation at pH 5.9. The current showed the permeability sequence for anions to be SCN Ϫ Ͼ Br Ϫ Ͼ I Ϫ Ͼ Cl Ϫ Ͼ F Ϫ Ͼ aspartate, while it exhibited a time-dependent activation at large positive potentials. Similar currents were also observed in mouse atrial cells and in atrial and ventricular cells from guinea pig. Some Cl Ϫ channel blockers (DIDS, niflumic acid, and glibenclamide) inhibited I Cl,acid, whereas tamoxifen had little effect on it. Unlike volume-regulated Cl Ϫ current (I Cl,vol) and CFTR Cl Ϫ current (ICl,CFTR), ICl,acid was independent of the presence of intracellular ATP. Activation of I Cl,acid appeared to be also independent of intracellular Ca 2ϩ and G protein. ICl,acid and I Cl,vol could develop in an additive fashion in acidic hypotonic solutions. Isoprenaline-induced I Cl,CFTR was inhibited by acidification in a pH-dependent manner in guinea pig ventricular cells. Our results support the view that I Cl,acid and ICl,vol stem from two distinct populations of anion channels and that the I Cl,acid channels are present in cardiac cells. I Cl,acid may play a role in the control of action potential duration or cell volume under pathological conditions, such as ischemia-related cardiac acidosis. acidosis; chloride channel; heart CHLORIDE (Cl Ϫ ) channels play a role in a variety of cell functions, such as cell cycle, apoptosis, ion homeostasis, cell volume regulation, and muscle tone (for review see Refs. 11,12,and 20). Several types of Cl Ϫ currents have been recorded in native cardiac cells (for review see Refs. 9 and 11). These include Cl Ϫ currents activated by intracellular PKA (I Cl,PKA ), PKC (I Cl,PKC ), Ca 2ϩ (I Cl,Ca ), extracellular ATP (I Cl,ATP ), or cell swelling (I Cl,vol ) and an inwardly rectifying Cl Ϫ current (I Cl,ir ). The channels responsible for I Cl,PKA , I Cl,PKC , and I Cl,ATP likely share the same molecular basis derived from CFTR gene, and thus these currents can be unified as I Cl,CFTR (11). It has been shown that some of these Cl Ϫ currents depend on extracellular pH (pH o ). Acidic pH o enhances I Cl,Ca in rabbit ventricular cells (10) and I Cl,ir in rat atrial and ventricular cells (13,14) and inhibits I Cl,CFTR in guinea pig ventricular cells (17). The roles of such pH o -dependent attenuation of Cl Ϫ currents in cardiac electrical activity under pathophysiological conditions have been investigated (9 -11, 13, 14).On the other hand, a more directly pH o -dependent regulation has been found in cultured cells. Auzanneau et al. (1) Recently, however, Lambert and Oberwinkler (15) extensively studied the properties of I Cl,acid and I Cl,vol in HEK293 cells. Their import...

Acidic pH-activated Cl- Current and Intracellular Ca2+ Response in Human Keratinocytes

“…The properties of ICl,pH in human keratinocytes are very similar to those reported in the above literatures; activation at pHe below 5.5 (room temperature), time-dependent kinetics, outward rectification, and high sensitivity to DIDS blocking (Nobles et al, 2004;Lambert et al, 2005;Yamamoto et al, 2006;Wang et al, 2007). In this respect, ICl,pH appears to be broadly expressed in mammalian cells, like volume-activated Cl current (ICl,vol).…”

“…The acidic pH-activated outward rectifying anion current similar to ICl,pH was firstly reported in rat Sertoli cells (Auzanneau et al, 2003) and subsequently in various types of cell lines (HEK-293, CHO, HeLa, PC-12, Caco-2 and HBE), hippocampal astrocytes and cardiac myocytes (Nobles et al, 2004;Lambert et al, 2005;Yamamoto et al, 2006;Wang et al, 2007). The properties of ICl,pH in human keratinocytes are very similar to those reported in the above literatures; activation at pHe below 5.5 (room temperature), time-dependent kinetics, outward rectification, and high sensitivity to DIDS blocking (Nobles et al, 2004;Lambert et al, 2005;Yamamoto et al, 2006;Wang et al, 2007).…”

Temperature sensitivity of acid-sensitive outwardly rectifying (ASOR) anion channels in cortical neurons is involved in hypothermic neuroprotection against acidotoxic necrosis

“…These biophysical and pharmacological properties of neuronal acid-activated currents are phenotypically identical to those of ASOR anion channel expressing in a variety of non-neuronal cells. [1][2][3][4][5][6][7][8][9][10] Since our previous study 11 showed high sensitivity of the human epithelial ASOR channel currents to temperature, we next observed the effects of continuous changes in temperature of the extracellular solution from 22 to 38 °C on the mouse neuronal ASOR channel currents recorded at pH 5.25. The currents gradually decreased and increased with reducing and raising the temperature, respectively (Fig.…”

“…[1][2][3][4][5][6][7][8][9][10] This channel is phenotypically characterized by activation by severe extracellular acidification alone as well as by strong outward rectification [1][2][3][4][5][6][7][8][9][10] and was shown to be involved in the genesis of acidotoxic necrotic cell death in human epithelial cells. 1 Our recent study 11 showed that the epithelial ASOR anion channel is sensitive to temperature.…”

The Functional Role of Chloride Channels in Cardiac Pacemaker Activity

“…A novel Cl -current activated by extracellular acidosis (I Cl.acid ) has also been observed in cardiac myocytes but the molecular identity for I Cl.acid is currently not known (Yamamoto & Ehara, 2006).…”