Structural Requirements of Membrane Phospholipids for M-type Potassium Channel Activation and Binding

Telezhkin, Vsevolod; Reilly, JM; Thomas, A.; Tinker, Andrew; Da, Brown

doi:10.1074/jbc.m111.322552

Cited by 35 publications

(40 citation statements)

References 40 publications

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“…Patches with some single-channel activity in the cellattached mode were excised into the inside-out configuration; upon excision, channel activity declined sharply, displaying almost no activity (Fig. 2 C-F), in accord with previous findings (6,27). This sharp rundown of channel activity upon patch excision is likely caused by the depletion of membrane PIP 2 by the membranebound lipid phosphatases present in the patch membrane and is characteristic of virtually all PIP 2 -sensitive ion channels (28).…”

Section: Resultssupporting

confidence: 89%

“…Another important point is that not only PIP 2 but also other phosphoinositides, such as PIP, PI(3,4)P, and PI(3,4,5)P (6,27), and even other phospholipids, such as lysophosphatidic acid and sphingosine-1-phosphate (27), can activate KCNQ channels. Under normal physiological circumstances these interactions are thought not to affect KCNQ channel activity significantly because of the low plasma membrane abundance of these other lipids relative to that of PIP 2 (2,27). However, should the affinity of channel-lipid interaction increase, these minor phospholipids may come into play.…”

Section: Discussionmentioning

confidence: 99%

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

Gao

Boillat

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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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Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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

Gao

Boillat

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…When active, these channels suppress depolarization by EPSPs and promote spike accommodation by enhancing the afterhyperpolarization (Brown and Yu, 2000). Importantly, M-current conductance by KCNQ channels depends on sufficient levels of PIP 2 , which is hydrolyzed by PLC (Suh and Hille, 2002;Suh et al, 2006;Telezhkin et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

M₁-Muscarinic Receptors Promote Fear Memory Consolidation via Phospholipase C and the M-Current

Young

Thomas

2014

J. Neurosci.

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Neuromodulators released during and after a fearful experience promote the consolidation of long-term memory for that experience. Because overconsolidation may contribute to the recurrent and intrusive memories of post-traumatic stress disorder, neuromodulatory receptors provide a potential pharmacological target for prevention. Stimulation of muscarinic receptors promotes memory consolidation in several conditioning paradigms, an effect primarily associated with the M 1 receptor (M 1 R). However, neither inhibiting nor genetically disrupting M 1 R impairs the consolidation of cued fear memory. Using the M 1 R agonist cevimeline and antagonist telenzepine, as well as M 1 R knock-out mice, we show here that M 1 R, along with ␤ 2 -adrenergic (␤ 2 AR) and D 5 -dopaminergic (D 5 R) receptors, regulates the consolidation of cued fear memory by redundantly activating phospholipase C (PLC) in the basolateral amygdala (BLA). We also demonstrate that fear memory consolidation in the BLA is mediated in part by neuromodulatory inhibition of the M-current, which is conducted by KCNQ channels and is known to be inhibited by muscarinic receptors. Manipulating the M-current by administering the KCNQ channel blocker XE991 or the KCNQ channel opener retigabine reverses the effects on consolidation caused by manipulating ␤ 2 AR, D 5 R, M 1 R, and PLC. Finally, we show that cAMP and protein kinase A (cAMP/PKA) signaling relevant to this stage of consolidation is upstream of these neuromodulators and PLC, suggesting an important presynaptic role for cAMP/PKA in consolidation. These results support the idea that neuromodulatory regulation of ion channel activity and neuronal excitability is a critical mechanism for promoting consolidation well after acquisition has occurred.

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“…It is also possible that other phospholipids maintain the WT current due to species-dependent differences in lipid specificity (47)(48)(49), which has not yet been examined in this channel.…”

Section: Discussionmentioning

confidence: 99%

Mutations in Nature Conferred a High Affinity Phosphatidylinositol 4,5-Bisphosphate-binding Site in Vertebrate Inwardly Rectifying Potassium Channels

Tang

Larry

Hendra

et al. 2015

Journal of Biological Chemistry

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Background: A native Kir channel in a distant relative of vertebrates interacts weakly with PIP 2 . Results: Mutagenesis restores the vertebrate channel sensitivity to PIP 2 in sponge channels. Conclusion: A basic residue in the tether helix of Kir is required for high affinity PIP 2 regulation. Significance: Evolution conferred a high affinity interaction of vertebrate Kir channels with PIP 2 , which is lacking in a distant relative.

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Structural Requirements of Membrane Phospholipids for M-type Potassium Channel Activation and Binding

Cited by 35 publications

References 40 publications

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

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

M₁-Muscarinic Receptors Promote Fear Memory Consolidation via Phospholipase C and the M-Current

Mutations in Nature Conferred a High Affinity Phosphatidylinositol 4,5-Bisphosphate-binding Site in Vertebrate Inwardly Rectifying Potassium Channels

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Structural Requirements of Membrane Phospholipids for M-type Potassium Channel Activation and Binding

Cited by 35 publications

References 40 publications

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

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

M1-Muscarinic Receptors Promote Fear Memory Consolidation via Phospholipase C and the M-Current

Mutations in Nature Conferred a High Affinity Phosphatidylinositol 4,5-Bisphosphate-binding Site in Vertebrate Inwardly Rectifying Potassium Channels

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M₁-Muscarinic Receptors Promote Fear Memory Consolidation via Phospholipase C and the M-Current