Channelopathies linked to plasma membrane phosphoinositides

Logothetis, Diomedes E.; Petrou, Vasileios I.; Adney, Scott K.; Mahajan, Rohit

doi:10.1007/s00424-010-0828-y

Cited by 89 publications

(87 citation statements)

References 229 publications

(150 reference statements)

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“…By reconfiguring the CaM ring underneath the pore, the cloud envelope in contact with PIP 2 at the inner leaflet of the membrane could change, such that the orientation of lysine, arginine or histidine residues making electrostatic contacts with the charged phosphate groups will be controlled at a distance by helix D. A fuzzy organization of the PIP 2 -binding surface like this may help to explain the puzzling similar effects in channel-PIP 2 sensitivity of low and elevated CaM levels. Defects in channel-PIP 2 sensitivity through interfering mutations can lead to disease (Logothetis et al, 2010). It is attractive to hypothesize that mutations not located at the binding site that disrupt channel-PIP 2 dependency, such as L609R described here and which was found in a patient with an epileptic condition (Richards et al, 2004), could also lead to disease.…”

Section: Discussionmentioning

confidence: 88%

Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation

Alberdi

Gomis-Pérez

Bernardo‐Seisdedos

et al. 2015

Journal of Cell Science

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We show that the combination of an intracellular bi-partite calmodulin (CaM)-binding site and a distant assembly region affect how an ion channel is regulated by a membrane lipid. Our data reveal that regulation by phosphatidylinositol(4,5)bisphosphate (PIP 2 ) and stabilization of assembled Kv7.2 subunits by intracellular coiled-coil regions far from the membrane are coupled molecular processes. Live-cell fluorescence energy transfer measurements and direct binding studies indicate that remote coiled-coil formation creates conditions for different CaM interaction modes, each conferring different PIP 2 dependency to Kv7.2 channels. Disruption of coiledcoil formation by epilepsy-causing mutation decreases apparent CaM-binding affinity and interrupts CaM influence on PIP 2 sensitivity.

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Section: Discussionmentioning

confidence: 88%

Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation

Alberdi

Gomis-Pérez

Bernardo‐Seisdedos

et al. 2015

Journal of Cell Science

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“…However, if a drug could target the PIP 2 -dependent coupling, it would amplify the current without losing these physiologically important characteristics. This is an exciting rationale for drug design that may be applicable to other PIP 2 -related ion channel diseases (48).…”

Section: Discussionmentioning

confidence: 99%

Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening

Zaydman

Silva

Delaloye

et al. 2013

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

177

313

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Voltage-gated ion channels generate dynamic ionic currents that are vital to the physiological functions of many tissues. These proteins contain separate voltage-sensing domains, which detect changes in transmembrane voltage, and pore domains, which conduct ions. Coupling of voltage sensing and pore opening is critical to the channel function and has been modeled as a protein-protein interaction between the two domains. Here, we show that coupling in Kv7.1 channels requires the lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ). We found that voltage-sensing domain activation failed to open the pore in the absence of PIP 2 . This result is due to loss of coupling because PIP 2 was also required for pore opening to affect voltage-sensing domain activation. We identified a critical site for PIP 2 -dependent coupling at the interface between the voltage-sensing domain and the pore domain. This site is actually a conserved lipid-binding site among different K + channels, suggesting that lipids play an important role in coupling in many ion channels.V oltage-gated ion channels are integral membrane proteins that sense membrane voltage and respond by opening or closing a transmembrane pore. Ionic currents carried by voltage-gated ion channels control contraction in muscle, encode information in the nervous system, and trigger secretion in neurohormonal tissues. Voltage-gated ion channels contain four voltage-sensing domains (VSDs) and a central pore domain (PD) that are structurally distinct (1, 2). In voltage-gated potassium (Kv) channels, the first four transmembrane segments (S1-S4) of each α-subunit forms a VSD. In response to changes in transmembrane voltage, the VSD undergoes a conformational change, called activation, during which membrane depolarization moves the S4 segment outward (3). The PD is formed by the last two transmembrane segments (S5, S6) from four α-subunits and undergoes a mainly voltageindependent conformational change during which the intracellular ends of the S6 segments bend, opening the ionic pore (4, 5). Interestingly, the PD and VSD can exist in pore-only (6) and voltage sensor-only proteins, respectively, where they function independently (7,8). Confining sensitivity to voltage, or to other stimuli, within a domain diversifies the ion channel properties that can be achieved by partnering different pore and sensor domains. However, this modular architecture also raises a fundamental question as to how VSD activation is transmitted to the PD. Previous studies of this coupling process have revealed the importance of direct protein-protein interactions at the VSD-PD interface (9-13); however, the possible role of membrane lipids in VSD-PD coupling remains undetermined.The membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ) modulates the activity of many ion channels, including some voltage-gated channels (14). Notably, all members of the Kv7 family (Kv7.1-Kv7.5), which play important physiological roles in the cardiac (15) or the nervous (16) systems, require PIP 2 to be opened by...

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“…PIP 2 is important for the functions of KCNQ channels. Reduction of PIP 2 affinity caused by congenic mutations of KCNQ channels is associated with long QT syndrome, suggesting critical physiological implications of PIP 2 on KCNQ channels (23,26). We reported that PIP 2 also alters the pharmacological selectivity of KCNQ potassium channels (6).…”

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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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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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Channelopathies linked to plasma membrane phosphoinositides

Cited by 89 publications

References 229 publications

Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation

Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation

Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening

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

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Channelopathies linked to plasma membrane phosphoinositides

Cited by 89 publications

References 229 publications

Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation

Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation

Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening

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

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