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

Sato-Numata, Kaori; Numata, Tomohiro; Okada, Yasunobu

doi:10.4161/chan.27748

Cited by 31 publications

(73 citation statements)

References 32 publications

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“…While it is possible that the acid-induced Cl − current resulted from enhanced activation of the constitutive Cl − current, it exhibited striking similarity to a group of previously discovered acid-induced Cl − currents [1], [8], [19], [40], [41], [47], [48], [53], [64], [65], [75], [78]. To further compare the MDCT currents, we studied the effects of NPPB (100 μM), DIDS (100 μM), and FFA (100 μM) on the acid-induced Cl − current (Fig.…”

Section: Resultsmentioning

confidence: 55%

Characterization of constitutive and acid-induced outwardly rectifying chloride currents in immortalized mouse distal tubular cells

Valinsky

Touyz

Shrier

2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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Thiazides block Na+ reabsorption while enhancing Ca2+ reabsorption in the kidney. As previously demonstrated in immortalized mouse distal convoluted tubule (MDCT) cells, chlorothiazide application induced a robust plasma membrane hyperpolarization, which increased Ca2+ uptake. This essential thiazide-induced hyperpolarization was prevented by the Cl− channel inhibitor 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), implicating NPPB-sensitive Cl− channels, however the nature of these Cl− channels has been rarely described in the literature. Here we show that MDCT cells express a dominant, outwardly rectifying Cl− current at extracellular pH 7.4. This constitutive Cl− current was more permeable to larger anions (Eisenman sequence I; I− > Br− ≥ Cl−) and was substantially inhibited by > 100 mM [Ca2+]o, which distinguished it from ClC-K2/barttin. Moreover, the constitutive Cl− current was blocked by NPPB, along with other Cl− channel inhibitors (4,4′-diisothiocyanatostilbene-2,2′-disulfonate, DIDS; flufenamic acid, FFA). Subjecting the MDCT cells to an acidic extracellular solution (pH < 5.5) induced a substantially larger outwardly rectifying NPPB-sensitive Cl− current. This acid-induced Cl− current was also anion permeable (I− > Br− > Cl−), but was distinguished from the constitutive Cl− current by its rectification characteristics, ion sensitivities, and response to FFA. In addition, we have identified similar outwardly rectifying and acid-sensitive currents in immortalized cells from the inner medullary collecting duct (mIMCD-3 cells). Expression of an acid-induced Cl− current would be particularly relevant in the acidic IMCD (pH < 5.5). To our knowledge, the properties of these Cl− currents are unique and provide the mechanisms to account for the Cl− efflux previously speculated to be present in MDCT cells.

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Section: Resultsmentioning

confidence: 55%

Characterization of constitutive and acid-induced outwardly rectifying chloride currents in immortalized mouse distal tubular cells

Valinsky

Touyz

Shrier

2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…8C). Agreeing with the hypothesis [14,27] that the parallel opening of ASOR and ASICs (acid-sensitive Na + -channels [38,39]) leads to an electrically coupled influx of osmotically active Na + and Cl -, WT cells swelled faster than TMEM206 −/− cells. Whereas WT cells subsequently decreased their volume, TMEM206 −/− cells failed to shrink (Fig.…”

Section: Role Of Tmem206/asor Channels In Acidotoxicitymentioning

confidence: 83%

“…This form of cell death had been attributed to cell swelling caused by osmotic gradients generated by ASOR-mediated Clinflux [14,27]. When exposed to pH o 4.2, both WT and TMEM206 −/− HEK cells increased their volume within the first three minutes as indicated by increased calcein fluorescence (Fig.…”

Section: Role Of Tmem206/asor Channels In Acidotoxicitymentioning

confidence: 95%

“…ASOR was suggested [14,27] to play a role in acidotoxicity because DIDS and phloretin, compounds inhibiting ASOR but also several other channels or transporters, reduced acid-induced necrotic cell death of HeLa cells [14] and cultured cortical neurons [27]. We exposed both WT HEK cells, and two separately derived TMEM206 −/− clones, for 2 hours to acidic medium (pH o 4.5) in the absence and presence of PS.…”

Section: Role Of Tmem206/asor Channels In Acidotoxicitymentioning

confidence: 99%

“…It was therefore proposed [14] that the channel rather plays a role in pathologies such as cancer or ischemic stroke in which pH o can drop to pH 6.5 or below [22][23][24][25][26]. Indeed, ASOR inhibitors blunted cell swelling and cell death provoked by prolonged exposure to acidic pH o [14,27], suggesting that ASOR-mediated chloride influx may worsen the outcome of ischemic stroke. It seems, however, counterintuitive that a channel that enhances cell death under pathological conditions confers an evolutionary advantage.…”

Section: Introductionmentioning

confidence: 99%

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Identification of TMEM206 proteins as pore of ASOR acid-sensitive chloride channels

Ullrich

Blin

Lazarow

et al. 2019

Preprint

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Acid-sensing ion channels have important functions in physiology and pathology, but the molecular composition of acid-activated anion channels had remained unclear. We now used a genome-wide siRNA screen to molecularly identify the widely expressed acid-sensitive outwardly-rectifying ASOR chloride channel. ASOR is formed by TMEM206 proteins which display two transmembrane domains (TMs) and are expressed at the plasma membrane. Ion permeation-changing mutations along the length of TM2 and at the end of TM1 suggest that these segments line ASOR's pore. While not belonging to a gene family, TMEM206 has orthologs in probably all vertebrates. Currents from evolutionarily distant orthologs share activation by protons, a feature essential for ASOR's role in acid-induced cell death. TMEM206 defines a novel class of ion channels. Its identification will help to understand its physiological roles and the diverse ways by which anion-selective pores can be formed.

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Physiological Functions of the Volume-Regulated Anion Channel VRAC/LRRC8 and the Proton-Activated Chloride Channel ASOR/TMEM206

Kostritskaia,

Klüssendorf,

Pan

et al. 2023

Handbook of Experimental Pharmacology

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

Cited by 31 publications

References 32 publications

Characterization of constitutive and acid-induced outwardly rectifying chloride currents in immortalized mouse distal tubular cells

Characterization of constitutive and acid-induced outwardly rectifying chloride currents in immortalized mouse distal tubular cells

Identification of TMEM206 proteins as pore of ASOR acid-sensitive chloride channels

Physiological Functions of the Volume-Regulated Anion Channel VRAC/LRRC8 and the Proton-Activated Chloride Channel ASOR/TMEM206

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