Electrostatic interaction of internal Mg2+ with membrane PIP2 Seen with KCNQ K+ channels.
Activity of KCNQ (Kv7) channels requires binding of phosphatidylinositol 4,5-bisphosphate (PIP(2)) from the plasma membrane. We give evidence that Mg(2+) and polyamines weaken the KCNQ channel-phospholipid interaction. Lowering internal Mg(2+) augmented inward and outward KCNQ currents symmetrically, and raising Mg(2+) 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 Mg(2+) 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 Igamma to accelerate synthesis of PIP(2) attenuated the sensitivity to polyvalent cations. We suggest that Mg(2+) and other polycations reduce the currents by electrostatic binding to the negative charges of PIP(2), competitively reducing the amount of free PIP(2) available for interaction with channels. The dose-response curves could be modeled by a competition model that reduces the pool of free PIP(2). This mechanism is likely to modulate many other PIP(2)-dependent ion channels and cellular processes.
Suh
Byung-Chang
BC
Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195, USA.
Hille
Bertil
B
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051658:KCNQ2 Potassium Channel / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051659:KCNQ3 Potassium Channel / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D015778:Minor Histocompatibility Antigens; D008954:Models, Biological; D009355:Neomycin / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism* / Q000494:pharmacology; D011107:Polylysine / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011700:Putrescine / Q000378:metabolism; D051381:Rats; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D055672:Static Electricity; D019789:Tetraethylammonium / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496918:Kcnq3 protein, rat; D015778:Minor Histocompatibility Antigens; D019269:Phosphatidylinositol 4,5-Diphosphate; D011073:Polyamines; D026902:Potassium Channel Blockers; D011107:Polylysine; D013096:Spermine; D019789:Tetraethylammonium; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase; D009355:Neomycin; D008274:Magnesium; D011188:Potassium; D013095:Spermidine; D011700:Putrescine