Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a

Olena Yermolaieva, A. Soren Leonard, Mikael K. Schnizler, Francois M. Abboud, Michael J. Welsh

Research output: Contribution to journalArticle

279 Citations (Scopus)

Abstract

Acid-sensing ion channel (ASIC) 1a subunit is expressed in synapses of central neurons where it contributes to synaptic plasticity. However, whether these channels can conduct Ca2+ and thereby raise the cytosolic Ca2+ concentration, [Ca2+]c, and possibly alter neuronal physiology has been uncertain. We found that extracellular acidosis opened ASIC1a channels, which provided a pathway for Ca2+ entry and elevated [Ca2+]c in wild-type, but not ASIC1 -/-, hippocampal neurons. Acid application also raised [Ca 2+]c and evoked Ca2+ currents in heterologous cells expressing ASIC1a. Although ASIC2a is also expressed in central neurons, neither ASIC2a homomultimeric channels nor ASIC1a/2a heteromultimers showed H+-activated [Ca2+]c elevation or Ca 2+ currents. Because extracellular acidosis accompanying cerebral ischemia contributes to neuronal injury, we tested the effect of acidosis on cell death measured as lactate dehydrogenase release. Eliminating ASIC1a from neurons or treating ASIC1a-expressing cells with the ASIC blocker amiloride attenuated acidosis-induced cell injury. These results indicate that ASIC1a provides a non-voltage-gated pathway for Ca2+ to enter neurons. Thus, it may provide a target for modulation of [Ca2+]c.

Original languageEnglish
Pages (from-to)6752-6757
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number17
DOIs
StatePublished - 27 Apr 2004

Fingerprint

Acid Sensing Ion Channels
Acidosis
Calcium
Neurons
Acid Sensing Ion Channel Blockers
Neuronal Plasticity
Amiloride
Wounds and Injuries
Brain Ischemia
L-Lactate Dehydrogenase
Synapses
Cell Death
Acids

Cite this

Yermolaieva, Olena ; Leonard, A. Soren ; Schnizler, Mikael K. ; Abboud, Francois M. ; Welsh, Michael J. / Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 17. pp. 6752-6757.
@article{3442eca3713c41ce9f13b37f2cdb6c65,
title = "Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a",
abstract = "Acid-sensing ion channel (ASIC) 1a subunit is expressed in synapses of central neurons where it contributes to synaptic plasticity. However, whether these channels can conduct Ca2+ and thereby raise the cytosolic Ca2+ concentration, [Ca2+]c, and possibly alter neuronal physiology has been uncertain. We found that extracellular acidosis opened ASIC1a channels, which provided a pathway for Ca2+ entry and elevated [Ca2+]c in wild-type, but not ASIC1 -/-, hippocampal neurons. Acid application also raised [Ca 2+]c and evoked Ca2+ currents in heterologous cells expressing ASIC1a. Although ASIC2a is also expressed in central neurons, neither ASIC2a homomultimeric channels nor ASIC1a/2a heteromultimers showed H+-activated [Ca2+]c elevation or Ca 2+ currents. Because extracellular acidosis accompanying cerebral ischemia contributes to neuronal injury, we tested the effect of acidosis on cell death measured as lactate dehydrogenase release. Eliminating ASIC1a from neurons or treating ASIC1a-expressing cells with the ASIC blocker amiloride attenuated acidosis-induced cell injury. These results indicate that ASIC1a provides a non-voltage-gated pathway for Ca2+ to enter neurons. Thus, it may provide a target for modulation of [Ca2+]c.",
author = "Olena Yermolaieva and Leonard, {A. Soren} and Schnizler, {Mikael K.} and Abboud, {Francois M.} and Welsh, {Michael J.}",
year = "2004",
month = "4",
day = "27",
doi = "10.1073/pnas.0308636100",
language = "English",
volume = "101",
pages = "6752--6757",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "17",

}

Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. / Yermolaieva, Olena; Leonard, A. Soren; Schnizler, Mikael K.; Abboud, Francois M.; Welsh, Michael J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 17, 27.04.2004, p. 6752-6757.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a

AU - Yermolaieva, Olena

AU - Leonard, A. Soren

AU - Schnizler, Mikael K.

AU - Abboud, Francois M.

AU - Welsh, Michael J.

PY - 2004/4/27

Y1 - 2004/4/27

N2 - Acid-sensing ion channel (ASIC) 1a subunit is expressed in synapses of central neurons where it contributes to synaptic plasticity. However, whether these channels can conduct Ca2+ and thereby raise the cytosolic Ca2+ concentration, [Ca2+]c, and possibly alter neuronal physiology has been uncertain. We found that extracellular acidosis opened ASIC1a channels, which provided a pathway for Ca2+ entry and elevated [Ca2+]c in wild-type, but not ASIC1 -/-, hippocampal neurons. Acid application also raised [Ca 2+]c and evoked Ca2+ currents in heterologous cells expressing ASIC1a. Although ASIC2a is also expressed in central neurons, neither ASIC2a homomultimeric channels nor ASIC1a/2a heteromultimers showed H+-activated [Ca2+]c elevation or Ca 2+ currents. Because extracellular acidosis accompanying cerebral ischemia contributes to neuronal injury, we tested the effect of acidosis on cell death measured as lactate dehydrogenase release. Eliminating ASIC1a from neurons or treating ASIC1a-expressing cells with the ASIC blocker amiloride attenuated acidosis-induced cell injury. These results indicate that ASIC1a provides a non-voltage-gated pathway for Ca2+ to enter neurons. Thus, it may provide a target for modulation of [Ca2+]c.

AB - Acid-sensing ion channel (ASIC) 1a subunit is expressed in synapses of central neurons where it contributes to synaptic plasticity. However, whether these channels can conduct Ca2+ and thereby raise the cytosolic Ca2+ concentration, [Ca2+]c, and possibly alter neuronal physiology has been uncertain. We found that extracellular acidosis opened ASIC1a channels, which provided a pathway for Ca2+ entry and elevated [Ca2+]c in wild-type, but not ASIC1 -/-, hippocampal neurons. Acid application also raised [Ca 2+]c and evoked Ca2+ currents in heterologous cells expressing ASIC1a. Although ASIC2a is also expressed in central neurons, neither ASIC2a homomultimeric channels nor ASIC1a/2a heteromultimers showed H+-activated [Ca2+]c elevation or Ca 2+ currents. Because extracellular acidosis accompanying cerebral ischemia contributes to neuronal injury, we tested the effect of acidosis on cell death measured as lactate dehydrogenase release. Eliminating ASIC1a from neurons or treating ASIC1a-expressing cells with the ASIC blocker amiloride attenuated acidosis-induced cell injury. These results indicate that ASIC1a provides a non-voltage-gated pathway for Ca2+ to enter neurons. Thus, it may provide a target for modulation of [Ca2+]c.

UR - http://www.scopus.com/inward/record.url?scp=2342595925&partnerID=8YFLogxK

U2 - 10.1073/pnas.0308636100

DO - 10.1073/pnas.0308636100

M3 - Article

C2 - 15082829

AN - SCOPUS:2342595925

VL - 101

SP - 6752

EP - 6757

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 17

ER -