Modulation of nucleotide sensitivity of ATP-sensitive potassium channels by phosphatidylinositol-4-phosphate 5-kinase

S. L. Shyng, A. Barbieri, A. Gumusboga, C. Cukras, L. Pike, J. N. Davis, P. D. Stahl, C. G. Nichols

Research output: Contribution to journalArticle

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Abstract

ATP-sensitive potassium channels (K(ATP) channels) regulate cell excitability in response to metabolic changes. K(ATP) channels are formed as a complex of a sulfonylurea receptor (SURx), a member of the ATP-binding cassette protein family, and an inward rectifier K+ channel subunit (Kir6.x). Membrane phospholipids, in particular phosphatidylinositol (PI) 4,5- bisphosphate (PIP2), activate K(ATP) channels and antagonize ATP inhibition of K(ATP) channels when applied to inside-out membrane patches. To examine the physiological relevance of this regulatory mechanism, we manipulated membrane PIP2 levels by expressing either the wild-type or an inactive form of PI-4-phosphate 5-kinase (PIP5K) in COSm6 cells and examined the ATP sensitivity of coexpressed K(ATP) channels. Channels from cells expressing the wild-type PIP5K have a 6-fold lower ATP sensitivity (K(1/2), the half maximal inhibitory concentration, 60 μM) than the sensitivities from control cells (K(1/2) ≃ 10 μM). An inactive form of the PIP5K had little effect on the K(1/2) of wild-type channels but increased the ATP-sensitivity of a mutant K(ATP) channel that has an intrinsically lower ATP sensitivity (from K(1/2) ≃ 450 μM to K(1/2) ≃ 100 μM), suggesting a decrease in membrane PIP2 levels as a consequence of a dominant-negative effect of the inactive PIP5K. These results show that PIP5K activity, which regulates PIP2 and PI- 3,4,5-P3 levels, is a significant determinant of the physiological nucleotide sensitivity of K(ATP) channels.

Original languageEnglish (US)
Pages (from-to)937-941
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number2
DOIs
StatePublished - Jan 18 2000

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