Protein Kinase A Modulates PLC-Dependent Regulation and PIP<sub>2</sub>-Sensitivity of K<sup>+</sup>Channels

Lopes, Coeli M.; Remon, Juan I.; Matavel, Alessandra; Sui, Jin; Keselman, Inna; Medei, Emiliano; Shen, Yu-Min; Rosenhouse‐Dantsker, Avia; Logothetis, Diomedes E.

doi:10.4161/chan.4322

Cited by 53 publications

(67 citation statements)

References 66 publications

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“…A previous study suggested a cross-talk between PKA and PIP 2 modulations of the I Ks channel (31). To examine whether phosphorylation of I Ks channel affects PIP 2 -dependent modulation, we studied the properties of the mutation S27D/S92D in KCNQ1 coexpressed with KCNE1, which has been shown to mimic the effects of PKA phosphorylation of I Ks channels (31,32). Consistent with previous results, we found that S27D/S92D affects I Ks function, including a shift of voltage-dependent activation to more negative voltages and slowing of deactivation kinetics (Fig.…”

Section: Discussionmentioning

confidence: 91%

“…I Ks channels are also modulated by β-adrenergic receptor stimulation due to the phosphorylation of residues S27 and S92 in KCNQ1 by protein kinase A (PKA) (30,31), which increases I Ks currents and shortens ventricular action potentials. Importantly, this phosphorylation of KCNQ1 alters channel function only with KCNE1 coexpression (32), indicating that, similar to PIP 2 modulation, the KCNE1 interaction with KCNQ1 is critical for the PKA-dependent modulation.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, this phosphorylation of KCNQ1 alters channel function only with KCNE1 coexpression (32), indicating that, similar to PIP 2 modulation, the KCNE1 interaction with KCNQ1 is critical for the PKA-dependent modulation. A previous study suggested a cross-talk between PKA and PIP 2 modulations of the I Ks channel (31). To examine whether phosphorylation of I Ks channel affects PIP 2 -dependent modulation, we studied the properties of the mutation S27D/S92D in KCNQ1 coexpressed with KCNE1, which has been shown to mimic the effects of PKA phosphorylation of I Ks channels (31,32).…”

Section: Discussionmentioning

confidence: 99%

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KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity

Li¹,

Zaydman²,

Wu³

et al. 2011

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

105

136

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Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) is necessary for the function of various ion channels. The potassium channel, I Ks , is important for cardiac repolarization and requires PIP 2 to activate. Here we show that the auxiliary subunit of I Ks , KCNE1, increases PIP 2 sensitivity 100-fold over channels formed by the pore-forming KCNQ1 subunits alone, which effectively amplifies current because native PIP 2 levels in the membrane are insufficient to activate all KCNQ1 channels. A juxtamembranous site in the KCNE1 C terminus is a key structural determinant of PIP 2 sensitivity. Long QT syndrome associated mutations of this site lower PIP 2 affinity, resulting in reduced current. Application of exogenous PIP 2 to these mutants restores wild-type channel activity. These results reveal a vital role of PIP 2 for KCNE1 modulation of I Ks channels that may represent a common mechanism of auxiliary subunit modulation of many ion channels.K CNQ1 α-subunits coassemble with KCNE1 β-subunits to form the cardiac slow-delayed rectifier channel, I Ks , which conducts a potassium current that is important for the termination of the cardiac action potential. Although exogenous expression of KCNQ1 alone is sufficient to produce a voltage-gated channel, coexpression of KCNE1 with KCNQ1 leads to changes in current properties to resemble the physiologically important cardiac I Ks current ( Fig. 1A) (1, 2). These changes include increased current amplitude, shift of the voltage dependence of activation toward more positive potentials, slowed activation and deactivation kinetics, and suppressed inactivation, all of which are essential for the physiological role of I Ks (3). After many years of investigation, it is still poorly understood how the KCNE1 peptide exerts such a dramatic effect on the I Ks current. Loss-offunction mutations in I Ks lead to delayed cardiac cell repolarization that manifests clinically as long QT (LQT) syndrome. Patients with LQT syndrome are predisposed to ventricular arrhythmia and suffer from syncope and a high risk of sudden cardiac death. At present, the molecular mechanisms of disease pathogenesis are still unknown for many LQT-associated mutations in I Ks .Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) is a minor acidic membrane lipid found primarily in the inner leaflet of the plasma membrane. PIP 2 has been shown to be a necessary cofactor for a wide variety of ion channels, e.g., voltage-gated K þ and Ca 2þ channels, transient receptor potential channels, inward rectifying K þ channels, and epithelial Na þ channels (4). Recently, I Ks has been shown to require PIP 2 for channel activity, and several LQTassociated mutations located in KCNQ1 have been suggested to decrease the PIP 2 affinity of I Ks (5, 6). Here we provide evidence that KCNE1, as a β-subunit, alters the function of I Ks by modulating the interaction between PIP 2 and the heteromeric ion channel complex. Knowledge of the molecular mechanisms of channel modulation by KCNE1 is of great importance as at least 36 LQT-associated muta...

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity

Li¹,

Zaydman²,

Wu³

et al. 2011

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

105

136

View full text Add to dashboard Cite

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“…The modulation is mediated by the physical interaction of yotiao with the distal helix D, which regulates I KS channel activity following phosphorylation or dephosphorylation of S27 at the N-terminus of KCNQ1 (Kurokawa et al, 2004). S92 at the N-terminus of KCNQ1 is also predicted to be phosphorylated (Lopes et al, 2007;Lundby et al, 2013). We and others have found a direct interaction between the C-termini of KCNQ1 and KCNE (Haitin et al, 2009;Zheng et al, 2010).…”

Section: Introductionmentioning

confidence: 79%

Long QT mutations disrupt IKS regulation by PKA and PIP2 at the same KCNQ1 helix C-KCNE1 interface

Dvir

Strulovich

Sachyani

et al. 2014

Journal of Cell Science

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KCNQ1 and KCNE1 co-assembly generates the I KS K + current, which is crucial to the cardiac action potential repolarization. Mutations in their corresponding genes cause long QT syndrome (LQT) and atrial fibrillation. The A-kinase anchor protein, yotiao (also known as AKAP9), brings the I KS channel complex together with signaling proteins to achieve regulation upon b1-adrenergic stimulation. Recently, we have shown that KCNQ1 helix C interacts with the KCNE1 distal C-terminus. We postulated that this interface is crucial for I KS channel modulation. Here, we examined the yet unknown molecular mechanisms of LQT mutations located at this intracellular intersubunit interface. All LQT mutations disrupted the internal KCNQ1-KCNE1 intersubunit interaction. LQT mutants in KCNQ1 helix C led to a decreased current density and a depolarizing shift of channel activation, mainly arising from impaired phosphatidylinositol-4,5-bisphosphate (PIP 2 ) modulation. In the KCNE1 distal C-terminus, the LQT mutation P127T suppressed yotiao-dependent cAMP-mediated upregulation of the I KS current, which was caused by reduced KCNQ1 phosphorylation at S27. Thus, KCNQ1 helix C is important for channel modulation by PIP 2 , whereas the KCNE1 distal C-terminus appears essential for the regulation of I KS by yotiao-mediated PKA phosphorylation.

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“…In different native cells and expression systems, TREK-1 activity at negative membrane potentials is low and the channel shows marked outward rectification and voltage-dependent activation (28, 93,99,211,247). Stimulation of the G i -coupled mGluR2 (194), mGluR4 (43), or ␣ 2A -adrenergic receptors (343) activated the expressed and native TREK currents, respectively.…”

Section: G Protein-coupled Receptors and Phosphorylationmentioning

confidence: 99%

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Enyedi

Czirják

2010

Physiological Reviews

776

769

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Two-pore domain K+ (K2P) channels give rise to leak (also called background) K+ currents. The well-known role of background K+ currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K2P channel types) that this primary hyperpolarizing action is not performed passively. The K2P channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K2P channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K2P channel family into the spotlight. In this review, we focus on the physiological roles of K2P channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.

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Protein Kinase A Modulates PLC-Dependent Regulation and PIP₂-Sensitivity of K⁺Channels

Cited by 53 publications

References 66 publications

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity

Long QT mutations disrupt IKS regulation by PKA and PIP2 at the same KCNQ1 helix C-KCNE1 interface

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

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Protein Kinase A Modulates PLC-Dependent Regulation and PIP2-Sensitivity of K+Channels

Cited by 53 publications

References 66 publications

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP 2 ) sensitivity of I Ks to modulate channel activity

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP 2 ) sensitivity of I Ks to modulate channel activity

Long QT mutations disrupt IKS regulation by PKA and PIP2 at the same KCNQ1 helix C-KCNE1 interface

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

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Protein Kinase A Modulates PLC-Dependent Regulation and PIP₂-Sensitivity of K⁺Channels

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels