Channels Providing a Calcium Source

Elizabeth M. Adler

Science's STKE, AAAS, Washington, DC 20005, USA

Gliomas--highly migratory brain malignancies derived from glia--express an unusual splice variant of BK channels (large conductance potassium channels independently activated by depolarization and calcium) whose activity may support migration of these diffusely infiltrating tumors. Noting that gliomas are not excitable and that global increases in intracellular calcium concentration ([Ca²⁺]_i) of sufficient magnitude to activate BK channels would be expected to influence numerous other Ca²⁺-dependent processes, Weaver et al. investigated the possibility that activation of glioma BK channels might depend on a nearby Ca²⁺ source. Immunofluorescence analysis of two glioma cell lines revealed that BK channels localized with lipid raft markers in "hot spots" at the protruding edges of cells. Furthermore, Western analysis of fractionated cell lysates indicated that BK channels were associated with a lipid raft fraction defined by the presence of caveolin-1. Treatment of U251 cells with methyl--cyclodextrin to disrupt lipid rafts led to BK channel redistribution and rapidly decreased whole-cell BK currents. This reduction in BK current was not associated with channel internalization, nor was it associated with a loss of BK channel sensitivity to a global increase in [Ca²⁺]_i. Pharmacological analysis indicated that inositol 1,4,5-trisphosphate receptors (IP₃Rs), which were present in BK-containing hot spots and lipid raft fractions but did not coimmunoprecipitate with BK channels, provided the calcium source for BK activation. Thus, the authors propose that the localization of BK channels to lipid rafts allows IP₃-mediated signaling pathways to activate BK channels and suggest that disruption of such pathways may provide a novel approach to inhibiting glioma migration.

A. K. Weaver, M. L. Olsen, M. B. McFerrin, H. Sontheimer, BK channels are linked to inositol 1,4,5-triphosphate receptors via lipid rafts. J. Biol. Chem. 282, 31558-31568 (2007). [Abstract] [Full Text]

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