title: Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels.
abstract: Pharmacological augmentation of neuronal KCNQ muscarinic (M) currents by drugs such as retigabine (RTG) represents a first-in-class therapeutic to treat certain hyperexcitatory diseases by dampening neuronal firing. Whereas all five potassium channel subtypes (KCNQ1-KCNQ5) are found in the nervous system, KCNQ2 and KCNQ3 are the primary players that mediate M currents. We investigated the plasticity of subtype selectivity by two M current effective drugs, retigabine and zinc pyrithione (ZnPy). Retigabine is more effective on KCNQ3 than KCNQ2, whereas ZnPy is more effective on KCNQ2 with no detectable effect on KCNQ3. In neurons, activation of muscarinic receptor signaling desensitizes effects by retigabine but not ZnPy. Importantly, reduction of phosphatidylinositol 4,5-bisphosphate (PIP2) causes KCNQ3 to become sensitive to ZnPy but lose sensitivity to retigabine. The dynamic shift of pharmacological selectivity caused by PIP2 may be induced orthogonally by voltage-sensitive phosphatase, or conversely, abolished by mutating a PIP2 site within the S4-S5 linker of KCNQ3. Therefore, whereas drug-channel binding is a prerequisite, the drug selectivity on M current is dynamic and may be regulated by receptor signaling pathways via PIP2.
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Pingzheng
authors: P
authors: Zhou
authors: Haibo
authors: H
authors: Yu
authors: Min
authors: M
authors: Gu
authors: Fa-jun
authors: FJ
authors: Nan
authors: Zhaobing
authors: Z
authors: Gao
authors: Min
authors: M
authors: Li
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D016466:CHO Cells; D002219:Carbamates / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D051659:KCNQ3 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D007641:Keratolytic Agents / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009942:Organometallic Compounds / Q000494:pharmacology; D010655:Phenylenediamines / Q000494:pharmacology; D019269:Phosphatidylinositol 4,5-Diphosphate; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C114401:Kcnq2 protein, mouse; C496917:Kcnq3 protein, mouse; D007641:Keratolytic Agents; D009419:Nerve Tissue Proteins; D009942:Organometallic Compounds; D010655:Phenylenediamines; D019269:Phosphatidylinositol 4,5-Diphosphate; D011725:Pyridines; C101866:ezogabine; C010423:pyrithione zinc
keywords: cardiac arrhythmias; chemical probe; gating modifier; hyperexcitability; pain
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