Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate

Abstract

M-type (Kv7, KCNQ) potassium channels are proteins that control the excitability of neurons and muscle cells. Many physiological and pathological mechanisms of excitation operate via the suppression of M channel activity or expression. Conversely, pharmacological augmentation of M channel activity is a recognized strategy for the treatment of hyperexcitability disorders such as pain and epilepsy. However, physiological mechanisms resulting in M channel potentiation are rare. Here we report that intracellular free zinc directly and reversibly augments the activity of recombinant and native M channels. This effect is mechanistically distinct from the known redoxdependent KCNQ channel potentiation. Interestingly, the effect of zinc cannot be attributed to a single histidine-or cysteine-containing zinc-binding site within KCNQ channels. Instead, zinc dramatically reduces KCNQ channel dependence on its obligatory physiological activator, phosphatidylinositol 4,5-bisphosphate (PIP 2 ). We hypothesize that zinc facilitates interactions of the lipid-facing interface of a KCNQ protein with the inner leaflet of the plasma membrane in a way similar to that promoted by PIP 2 . Because zinc is increasingly recognized as a ubiquitous intracellular second messenger, this discovery might represent a hitherto unknown native pathway of M channel modulation and provide a fresh strategy for the design of M channel activators for therapeutic purposes.+ channels are a family of voltagegated K + channels with a very distinctive and robust role in the control of cellular excitability. The channels give rise to noninactivating K + currents with slow kinetics and a very negative activation threshold (−60 mV or even more negative). In combination, these features allow KCNQ channels to remain partially active at voltages near the resting membrane potential of a neuron or a muscle cell and thus strongly influence excitability (1, 2). Transient KCNQ channel inhibition leads to reversible increases in neuronal excitability, whereas long-term losses of KCNQ channel activity often result in debilitating excitability disorders (1, 2). Thus, loss-of-function mutations within KCNQ genes underlie some types of epilepsy, deafness, and arrhythmias, whereas transcriptional down-regulation in sensory nerves may result in chronic pain (2). Conversely, M channel enhancers ("openers") reduce excitability and are clinically used as antiepileptic drugs (e.g., retigabine) or analgesics (e.g., flupirtine) (3). The therapeutic utility of KCNQ channel openers extends to other disorders linked to deregulated excitability, such as anxiety, stroke, and smooth muscle disorders (2, 3); therefore a global quest for specific and selective KCNQ openers is currently underway (3).The KCNQ channel family contains five members, KCNQ1-5 (Kv7.1-Kv7.5). KCNQ1 is expressed mostly within the cardiovascular system, whereas the other members are predominantly neuronal (1, 2). The most abundant M-type channel within the nervous system is believed to be the heteromeric KCNQ2/3 chan...

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