O2 deprivation inhibits Ca2+-activated K+ channels via cytosolic factors in mice neocortical neurons

AUTOR(ES)

Liu, Huajun

FONTE

American Society for Clinical Investigation

RESUMO

O2 deprivation induces membrane depolarization in mammalian central neurons. It is possible that this anoxia-induced depolarization is partly mediated by an inhibition of K+ channels. We therefore performed experiments using patch-clamp techniques and dissociated neurons from mice neocortex. Three types of K+ channels were observed in both cell-attached and inside-out configurations, but only one of them was sensitive to lack of O2. This O2-sensitive K+ channel was identified as a large-conductance Ca2+-activated K+ channel (BKCa), as it exhibited a large conductance of 210 pS under symmetrical K+ (140 mM) conditions, a strong voltage-dependence of activation, and a marked sensitivity to Ca2+. A low-O2 medium (PO2 = 10–20 mmHg) markedly inhibited this BKCa channel open probability in a voltage-dependent manner in cell-attached patches, but not in inside-out patches, indicating that the effect of O2 deprivation on BKCa channels of mice neocortical neurons was mediated via cytosol-dependent processes. Lowering intracellular pH (pHi), or cytosolic addition of the catalytic subunit of a cAMP-dependent protein kinase A in the presence of Mg-ATP, caused a decrease in BKCa channel activity by reducing the sensitivity of this channel to Ca2+. In contrast, the reducing agents glutathione and DTT increased single BKCa channel open probability without affecting unitary conductance. We suggest that in neocortical neurons, (a) BKCa is modulated by O2 deprivation via cytosolic factors and cytosol-dependent processes, and (b) the reduction in channel activity during hypoxia is likely due to reduced Ca2+ sensitivity resulting from cytosolic alternations such as in pHi and phosphorylation. Because of their large conductance and prevalence in the neocortex, BKCa channels may be considered as a target for pharmacological intervention in conditions of acute anoxia or ischemia.

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