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Acidosis decreases low Ca 2+ ‐induced neuronal excitation by inhibiting the activity of calcium‐sensing cation channels in cultured mouse hippocampal neurons
Author(s) -
Chu XiangPing,
Zhu XiaoMan,
Wei WenLi,
Li GuoHua,
Simon Roger P.,
MacDonald John F.,
Xiong ZhiGang
Publication year - 2003
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2003.043091
Subject(s) - depolarization , biophysics , extracellular , chemistry , intracellular ph , amiloride , intracellular , patch clamp , membrane potential , voltage clamp , hippocampal formation , reversal potential , calcium , electrophysiology , biochemistry , endocrinology , biology , neuroscience , sodium , receptor , organic chemistry
The effects of extracellular pH (pH o ) on calcium‐sensing non‐selective cation (csNSC) channels in cultured mouse hippocampal neurons were investigated using whole‐cell voltage‐clamp and current‐clamp recordings. Decreasing extracellular Ca 2+ concentrations ([Ca 2+ ] o ) activated slow and sustained inward currents through the csNSC channels. Decreasing pH o activated amiloride‐sensitive transient proton‐gated currents which decayed to baseline in several seconds. With proton‐gated channels inactivated by pre‐perfusion with low pH solution or blocked by amiloride, decreasing pH o to 6.5 inhibited the csNSC currents with a leftward shift of the Ca 2+ dose–inhibition curve. Increasing pH to 8.5, on the other hand, caused a rightward shift of the Ca 2+ dose–inhibition curve and potentiated the csNSC currents. Intracellular alkalinization following bath perfusion of quinine mimicked the potentiation of the csNSC currents by increasing pH o , while intracellular acidification by addition and subsequent withdrawal of NH 4 Cl mimicked the inhibition of the csNSC currents by decreasing pH o . Intracellular pH (pH i ) imaging demonstrated that decreasing pH o induced a corresponding decrease in pH i . Including 30 mM Hepes in the pipette solution eliminated the effects of quinine and NH 4 Cl on the csNSC currents, but only partially reduced the effect of lowering pH o . In current‐clamp recordings, decreasing [Ca 2+ ] o induced sustained membrane depolarization and excitation of hippocampal neurons. Decreasing pH o to 6.5 inhibited the low [Ca 2+ ] o ‐induced csNSC channel‐mediated membrane depolarization and the excitation of neurons. Our results indicate that acidosis may inhibit low [Ca 2+ ] o ‐induced neuronal excitation by inhibiting the activity of the csNSC channels. Both the extracellular and the intracellular sites are involved in the proton modulation of the csNSC channels.