Relationship between Membrane Phosphatidylinositol-4,5-Bisphosphate and Receptor-Mediated Inhibition of Native Neuronal M Channels

Winks, Joanna Shaw; Hughes, Simon; Filippov, Alexander K.; Tatulian, Lucine; Abogadie, Fe C.; Brown, David A.; Marsh, Stephen J.

doi:10.1523/jneurosci.3231-04.2005

Cited by 156 publications

(242 citation statements)

References 63 publications

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“…A phosphatidylinositol-5-kinase (PI5-K) was coexpressed with the KCNQ2 channel. Overexpression of PI5-K can elevate the PIP 2 membrane concentration to millimolar levels (17). When coexpressed with PI5-K, the current amplitude of the KCNQ2 channel at +50 mV (saturated voltage potential) is significantly higher than the control ( Fig.…”

Section: Resultsmentioning

confidence: 90%

“…Structural studies on Kir channels (1,2,5) demonstrated that PIP 2 directly interacts with the channels. Subsequent studies supported that PIP 2 also interacts directly with voltage-gated potassium (Kv) channels (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Several positive residues that may be critical for PIP 2 activity have been identified (7,11,18,(20)(21)(22)(23)(24).…”

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confidence: 99%

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Dynamic PIP ₂ interactions with voltage sensor elements contribute to KCNQ2 channel gating

Zhang

Zhou

Chen

et al. 2013

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

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The S4 segment and the S4-S5 linker of voltage-gated potassium (Kv) channels are crucial for voltage sensing. Previous studies on the Shaker and Kv1.2 channels have shown that phosphatidylinositol-4,5-bisphosphate (PIP 2 ) exerts opposing effects on Kv channels, upregulating the current amplitude, while decreasing the voltage sensitivity. Interactions between PIP 2 and the S4 segment or the S4-S5 linker in the closed state have been highlighted to explain the effects of PIP 2 on voltage sensitivity. Here, we show that PIP 2 preferentially interacts with the S4-S5 linker in the open-state KCNQ2 (Kv7.2) channel, whereas it contacts the S2-S3 loop in the closed state. These interactions are different from the PIP 2 -Shaker and PIP 2 -Kv1.2 interactions. Consistently, PIP 2 exerts different effects on KCNQ2 relative to the Shaker and Kv1.2 channels; PIP 2 up-regulates both the current amplitude and voltage sensitivity of the KCNQ2 channel. Disruption of the interaction of PIP 2 with the S4-S5 linker by a single mutation decreases the voltage sensitivity and current amplitude, whereas disruption of the interaction with the S2-S3 loop does not alter voltage sensitivity. These results provide insight into the mechanism of PIP 2 action on KCNQ channels. In the closed state, PIP 2 is anchored at the S2-S3 loop; upon channel activation, PIP 2 interacts with the S4-S5 linker and is involved in channel gating.A series of ion channels, such as inward rectifier K + (Kir) channels, transient receptor potential channels, and voltagegated channels, are sensitive to the presence of phosphatidylinositol-4,5-bisphosphate (PIP 2 ) in membranes (1-4). Structural studies on Kir channels (1, 2, 5) demonstrated that PIP 2 directly interacts with the channels. Subsequent studies supported that PIP 2 also interacts directly with voltage-gated potassium (Kv) channels (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Several positive residues that may be critical for PIP 2 activity have been identified (7,11,18,(20)(21)(22)(23)(24). Previous studies on Kv1.2 and Shaker channels showed that PIP 2 exerts opposing effects on Kv channels, up-regulating the current amplitude, while leading to a decrease in voltage sensitivity (7, 18). The S4 segment and the S4-S5 linker of Kv channels are crucial for voltage sensing. The interactions of PIP 2 with the S4 segments and the S4-S5 linkers of the closed-state Shaker and Kv1.2 channels underlie the loss-of-function effect of PIP 2 on voltage sensitivity (7, 18).The KCNQ (Kv7) family of slowly activated outwardly rectifying potassium channels is one of the Kv channel families that are sensitive to the presence of PIP 2 in the membrane. KCNQ channels have been widely studied because of their important biological and pharmacological functions. Retigabine, a first-inclass K + channel opener used for the treatment of epilepsy, adopts a unique mechanism to enhance the activity of KCNQ channels (25). PIP 2 is important for the functions of KCNQ channels. Reduction of PIP 2 affinity caused by congenic mut...

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Section: Resultsmentioning

confidence: 90%

mentioning

confidence: 99%

Dynamic PIP ₂ interactions with voltage sensor elements contribute to KCNQ2 channel gating

Zhang

Zhou

Chen

et al. 2013

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

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“…Finally, the modulation of the M-current by muscarinic agonists in sympathetic SCG neurons has been thoroughly studied, and it is generally accepted that the depletion of PIP 2 (phosphatidylinositol 4,5-bisphosphate) accounts for the M-current inhibition (Suh and Hille, 2002;Winks et al, 2005). Recently, muscarinic inhibition of TREK-2 channels was reported in a heterologous system , and it is tempting to speculate that the increase in excitability provoked by muscarinic agonists in mSCG neurons may, at least in part, be attributable to this inhibition.…”

Section: Physiological Role Of Trek Channels In Sympathetic Neuronsmentioning

confidence: 99%

Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

Cadaveira-Mosquera¹,

Ribeiro²,

Reboreda³

et al. 2011

J. Neurosci.

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ϩ channel) mRNA, and the expression of these three proteins was confirmed by immunocytochemistry in mSCG neurons. I RIL was enhanced by zinc, inhibited by barium and fluoxetine, but unaffected by quinine and ruthenium red, strongly suggesting that it was carried through TREK-1/2 channels. Consistently, a channel with properties identical with the heterologously expressed TREK-2 was recorded in most (75%) cell-attached patches. These results provide the first evidence for the expression of K2P channels in the mammalian autonomic nervous system, and they extend the impact of these channels to the entire nervous system.

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“…Activation of G-protein-coupled receptors of the Gq/11 family strongly suppresses M-channels (Delmas and Brown, 2005), via depletion of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) upon muscarinic receptor stimulation (Suh and Hille, 2002;Ford et al, 2003;Zhang et al, 2003;Suh et al, 2004;Winks et al, 2005) or via Ca 2ϩ -calmodulin (CaM) action on the channels upon bradykinin B 2 and purinergic P 2 Y receptor activation (Cruzblanca et al, 1998;Bofill-Cardona et al, 2000;Gamper and Shapiro, 2003;Zaika et al, 2007). Recently, syntaxin 1A (Syx), a plasma membrane protein component of the exocytotic SNARE complex, shown to interact physically and functionally with different voltage-gated K ϩ channels (Fili et al, 2001;Leung et al, 2003Leung et al, , 2007Michaelevski et al, 2003Michaelevski et al, , 2007Tsuk et al, 2005;Yamakawa et al, 2007;Regev et al, 2009), was suggested to be another blocker of M-channels (Regev et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Neuronal M-Channel Gating in an Isoform-Specific Manner: Functional Interplay between Calmodulin and Syntaxin 1A

Etzioni¹,

Siloni²,

Chikvashvilli³

et al. 2011

J. Neurosci.

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Whereas neuronal M-type Kϩ channels composed of KCNQ2 and KCNQ3 subunits regulate firing properties of neurons, presynaptic KCNQ2 subunits were demonstrated to regulate neurotransmitter release by directly influencing presynaptic function. Two interaction partners of M-channels, syntaxin 1A and calmodulin, are known to act presynaptically, syntaxin serving as a major protein component of the membrane fusion machinery and calmodulin serving as regulator of several processes related to neurotransmitter release. Notably, both partners specifically modulate KCNQ2 but not KCNQ3 subunits, suggesting selective presynaptic targeting to directly regulate exocytosis without interference in neuronal firing properties. Here, having first demonstrated in Xenopus oocytes, using analysis of single-channel biophysics, that both modulators downregulate the open probability of KCNQ2 but not KCNQ3 homomers, we sought to resolve the channel structural determinants that confer the isoform-specific gating downregulation and to get insights into the molecular events underlying this mechanism. We show, using optical, biochemical, electrophysiological, and molecular biology analyses, the existence of constitutive interactions between the N and C termini in homomeric KCNQ2 and KCNQ3 channels in living cells. Furthermore, rearrangement in the relative orientation of the KCNQ2 termini that accompanies reduction in single-channel open probability is induced by both regulators, strongly suggesting that closer N-C termini proximity underlies gating downregulation. Different structural determinants, identified at the N and C termini of KCNQ3, prevent the effects by syntaxin 1A and calmodulin, respectively. Moreover, we show that the syntaxin 1A and calmodulin effects can be additive or blocked at different concentration ranges of calmodulin, bearing physiological significance with regard to presynaptic exocytosis.

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Relationship between Membrane Phosphatidylinositol-4,5-Bisphosphate and Receptor-Mediated Inhibition of Native Neuronal M Channels

Cited by 156 publications

References 63 publications

Dynamic PIP ₂ interactions with voltage sensor elements contribute to KCNQ2 channel gating

Dynamic PIP ₂ interactions with voltage sensor elements contribute to KCNQ2 channel gating

Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

Regulation of Neuronal M-Channel Gating in an Isoform-Specific Manner: Functional Interplay between Calmodulin and Syntaxin 1A

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Relationship between Membrane Phosphatidylinositol-4,5-Bisphosphate and Receptor-Mediated Inhibition of Native Neuronal M Channels

Cited by 156 publications

References 63 publications

Dynamic PIP 2 interactions with voltage sensor elements contribute to KCNQ2 channel gating

Dynamic PIP 2 interactions with voltage sensor elements contribute to KCNQ2 channel gating

Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

Regulation of Neuronal M-Channel Gating in an Isoform-Specific Manner: Functional Interplay between Calmodulin and Syntaxin 1A

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Dynamic PIP ₂ interactions with voltage sensor elements contribute to KCNQ2 channel gating

Dynamic PIP ₂ interactions with voltage sensor elements contribute to KCNQ2 channel gating