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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 and C. G. Nichols
Proceedings of the National Academy of Sciences of the United States of America
Vol. 97, No. 2 (Jan. 18, 2000), pp. 937-941
Stable URL: http://www.jstor.org/stable/121726
Page Count: 5
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Modulation of Nucleotide Sensitivity of ATP-Sensitive Potassium Channels by Phosphatidylinositol-4-Phosphate 5-Kinase
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Abstract

ATP-sensitive potassium channels (KATPchannels) regulate cell excitability in response to metabolic changes. KATP 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 KATP channels and antagonize ATP inhibition of KATP 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 KATP channels. Channels from cells expressing the wild-type PIP5K have a 6-fold lower ATP sensitivity (K1/2, the half maximal inhibitory concentration,≈ 60 μ M) than the sensitivities from control cells (K1/2≈ 10 μ M). An inactive form of the PIP5K had little effect on the K1/2 of wild-type channels but increased the ATP-sensitivity of a mutant KATP channel that has an intrinsically lower ATP sensitivity (from K1/2≈ 450 μ M to K1/2≈ 100 μ M), 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 KATP channels.

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