Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a.
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 Ca(2+) and thereby raise the cytosolic Ca(2+) concentration, [Ca(2+)](c), and possibly alter neuronal physiology has been uncertain. We found that extracellular acidosis opened ASIC1a channels, which provided a pathway for Ca(2+) entry and elevated [Ca(2+)](c) in wild-type, but not ASIC1(-/-), hippocampal neurons. Acid application also raised [Ca(2+)](c) and evoked Ca(2+) 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 [Ca(2+)](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 Ca(2+) to enter neurons. Thus, it may provide a target for modulation of [Ca(2+)](c).
Yermolaieva
Olena
O
Department of Internal Medicine and Physiology, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Leonard
A Soren
AS
Schnizler
Mikael K
MK
Abboud
Francois M
FM
Welsh
Michael J
MJ
D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000502:physiology*
D062565:Acid Sensing Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D007770:L-Lactate Dehydrogenase; D002118:Calcium