Activity of BKCa Channel Is Modulated by Membrane Cholesterol Content and Association with Na+/K+-ATPase in Human Melanoma IGR39 Cells

作者：Tajima Nobuyoshi; Itokazu Yutaka; Korpi Esa R; Somerharju Pentti; Kakela Reijo^*

来源：Journal of Biological Chemistry, 2011, 286(7): 5624-5638.

DOI：10.1074/jbc.M110.149898

Interaction of large conductance Ca2+- and voltage-activated K+ ( BKCa) channels with Na+/K+-ATPase, caveolin-1, and cholesterol was studied in human melanoma IGR39 cells. Functional BKCa channels were enriched in caveolin-rich and detergent-resistant membranes, i.e. rafts, and blocking of the channels by a specific BKCa blocker paxilline reduced proliferation of the cells. Disruption of rafts by selective depletion of cholesterol released BKCa channels from these domains with a consequent increase in their activity. Consistently, cholesterol enrichment of the cells increased the proportion of BKCa channels in rafts and decreased their activity. Immunocytochemical analysis showed that BKCa channels co-localize with Na+/K+-ATPase in a cholesterol-dependent manner, thus suggesting their co-presence in rafts. Supporting this, ouabain, a specific blocker of Na+/K+-ATPase, inhibited BKCa whole-cell current markedly in control cells but not in cholesterol-depleted ones. This inhibition required the presence of external Na+. Collectively, these data indicate that the presence of Na+/K+-ATPase in rafts is essential for efficient functioning of BKCa channels, presumably because the pump maintains a low intracellular Na+ proximal to the BKCa channel. In conclusion, cholesterol could play an important role in cellular ion homeostasis and thus modulate many cellular functions and cell proliferation.

• 出版日期2011-2-18