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Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195

Correspondence to Bertil Hille: hille{at}u.washington.edu

Activity of KCNQ (Kv7) channels requires binding of phosphatidylinositol 4,5-bisphosphate (PIP₂) from the plasma membrane. We give evidence that Mg²⁺ and polyamines weaken the KCNQ channel–phospholipid interaction. Lowering internal Mg²⁺ augmented inward and outward KCNQ currents symmetrically, and raising Mg²⁺ reduced currents symmetrically. Polyvalent organic cations added to the pipette solution had similar effects. Their potency sequence followed the number of positive charges: putrescine (+2) < spermidine (+3) < spermine (+4) < neomycin (+6) < polylysine (>>+6). The inhibitory effects of Mg²⁺ were reversible with sequential whole-cell patching. Internal tetraethylammonium ion (TEA) gave classical voltage-dependent block of the pore with changes of the time course of K⁺ currents. The effect of polyvalent cations was simpler, symmetric, and without changes of current time course. Overexpression of phosphatidylinositol 4-phosphate 5-kinase I to accelerate synthesis of PIP₂ attenuated the sensitivity to polyvalent cations. We suggest that Mg²⁺ and other polycations reduce the currents by electrostatic binding to the negative charges of PIP₂, competitively reducing the amount of free PIP₂ available for interaction with channels. The dose–response curves could be modeled by a competition model that reduces the pool of free PIP₂. This mechanism is likely to modulate many other PIP₂-dependent ion channels and cellular processes.

Abbreviations used in this paper: IP₃, inositol 1,4,5-trisphosphate; PIP, phosphatidylinositol 4-phosphate; PIP₂, phosphatidylinositol 4,5-bisphosphate; Oxo-M, oxotremorine-M; TEA, tetraethylammonium ion; PIPKI, phosphatidylinositol 4-phosphate 5-kinase I.

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