Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2

Li, Wu; Bauer, Claudia S.; Zhen, Xiao-guang; Xie, Cheng; Yang, Jian

doi:10.1038/nature01118

Cited by 226 publications

(273 citation statements)

References 29 publications

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“…The dual effect of PIP 2 on voltage sensitivity and on the stability of the open state also has been shown for voltage-gated Nand P/Q-type Ca 2+ channels (32). Although currently untested, it is possible that the S4-S5 linker of Ca v channels, as in Kv channels, is critically involved in mediating the effects of PIP 2 .…”

Section: Discussionmentioning

confidence: 99%

PIP ₂ controls voltage-sensor movement and pore opening of Kv channels through the S4–S5 linker

Rodríguez-Menchaca

Adney

Tang

et al. 2012

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

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Voltage-gated K + (Kv) channels couple the movement of a voltage sensor to the channel gate(s) via a helical intracellular region, the S4-S5 linker. A number of studies link voltage sensitivity to interactions of S4 charges with membrane phospholipids in the outer leaflet of the bilayer. Although the phospholipid phosphatidylinositol-4,5-bisphosphate (PIP 2 ) in the inner membrane leaflet has emerged as a universal activator of ion channels, no such role has been established for mammalian Kv channels. Here we show that PIP 2 depletion induced two kinetically distinct effects on Kv channels: an increase in voltage sensitivity and a concomitant decrease in current amplitude. These effects are reversible, exhibiting distinct molecular determinants and sensitivities to PIP 2 . Gating current measurements revealed that PIP 2 constrains the movement of the sensor through interactions with the S4-S5 linker. Thus, PIP 2 controls both the movement of the voltage sensor and the stability of the open pore through interactions with the linker that connects them.voltage-gated channels | lipids | channel modulation | open probability V oltage-gated K + (Kv) channels are tetrameric integral membrane proteins critical to membrane excitability that respond rapidly to changes in membrane potential to control membrane permeability to potassium ions. Upon membrane depolarization, a voltage sensor in each subunit undergoes a transition from a resting to an activated state followed by a concerted transition leading to the opening of the pore (1-4). The voltage-sensing domain [i.e., the S1-S4 transmembrane (TM) helices] of Kv channel subunits harbors within its S4 helix several positively charged residues that respond directly to changes in membrane voltage (5-7). The movement of these charges can be monitored by the gating current they produce, and the opening of the pore is monitored by the ionic current that follows. The S4-S5 linker couples the movement of the voltage sensor to the opening of the pore.X-ray structures of Kv channels have shown that the S1-S4 voltage-sensing domains are exposed to lipids when embedded in a membrane (8,9). A number of studies have suggested that, after depolarization, interactions of the S4 charges with lipids in the outer leaflet of the membrane are important in the stabilization of the sensor in the activated state (10-12).Phosphatidylinositol-4,5-bisphosphate (PIP 2 ), a phospholipid that affects the activity of many types of ion channels (13, 14), acts as a docking platform for the N-terminal domain of fastinactivating Kv channels (15). Activation of Ciona intestinalis voltage-sensitive phosphatase (Ci-VSP), which contains a voltage-sensing domain (S1-S4) coupled to a cytoplasmic phosphatase domain rather than a TM pore, shows a dependence on membrane depolarization similar to that of voltage-gated channels (16). PIP 2 modulates the motions of the Ci-VSP voltagesensor domain and its coupling to the phosphatase domain by interacting with the linker that connects the voltage sensor and phosphatase...

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Section: Discussionmentioning

confidence: 99%

PIP ₂ controls voltage-sensor movement and pore opening of Kv channels through the S4–S5 linker

Rodríguez-Menchaca

Adney

Tang

et al. 2012

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

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“…SCG neurons were studied under perforated patch whole-cell voltage clamp and were pretreated with the G o/i blocker, pertussis toxin, to isolate G q/11 -mediated actions (42). Our previous work reported suppression of I Ca by muscarinic M 1 receptors, but not bradykinin B 2 or purinergic P2Y receptors, via depletion of PIP 2 molecules in the membrane, which are necessary for Ca 2ϩ channel activity (10,11,14). Thus, the Ca 2ϩ channels act as a PIP 2 biosensor, and depression of I Ca reports depletion of PIP 2 .…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the I Ca in these cells makes an ideal biosensor of PIP 2 depletion by receptors, similar to the reporting by highly PIP 2 -sensitive GIRK K ϩ channels when expressed in the same neurons (9). It is important to note that such dramatic receptor specificity is only seen in native cells (23,(62)(63)(64)(65)(66)(67) and is wholly absent in reconstituted systems in which channels and receptors are heterologously expressed, in which all PLC-linked receptors elicit large Ca 2ϩ i signals and all probably work similarly (8,11,68,69).…”

Section: Discussionmentioning

confidence: 99%

Combined Phosphoinositide and Ca2+ Signals Mediating Receptor Specificity toward Neuronal Ca2+ Channels

Zaika

Zhang

Shapiro

2011

Journal of Biological Chemistry

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Phosphoinositides comprise a diverse array of plasma membrane signaling molecules with temporal effects ranging from 1 ms to the lifetime of the organism. Most intensively studied are the polyphosphorylated phosphatidylinositols (PIs). 2 The species phosphorylated at the 4Ј-and 5Ј-positions of the inositol ring by PI 4-kinase and PI 4-phosphate (PI(4)P) 5-kinase, called PI 4,5-bisphosphate (PIP 2 ), have been implicated as a critical player in myriad cellular activities. These include cytoskeletal remodeling, vesicular/protein trafficking among intracellular membranes, transcriptional control, and regulation of ion channels and transporters. Regarding the latter role, a large and widening array of such membrane transport proteins have been shown to be regulated by plasma membrane PIP 2 , presumably due to direct binding (1, 2). The action is thought to arise from either PIP 2 depletion by stimulation of phospholipase C (PLC)-coupled receptors or from alterations in the affinity of PIP 2 for the channels caused by generation of other signaling molecules (3). Using sympathetic neurons of the superior cervical ganglion (SCG) as a model, we have focused on PIP 2 -mediated regulation of voltage-gated "M-type" (KCNQ) K ϩ and "N-type" Ca 2ϩ currents. The former is so named for its depression by muscarinic stimulation, whose mechanism has been established as being due to depletion of PIP 2 (4 -9). The latter is also PIP 2 -sensitive (10 -12) as well as sensitive to arachidonic acid (13), and stimulation of PLC-linked muscarinic receptors likewise depresses I Ca in the same neurons (10,14). However, stimulation of other PLC-linked receptors (bradykinin B 2 and purinergic P2Y) in those neurons does not deplete PIP 2 and displays a pattern of M-current depression via intracellular Ca 2ϩ (Ca 2ϩ i ) signals (15, 16), acting on KCNQ channels via calmodulin (CaM) (17, 18), and little action on the N-type I Ca (10, 14) (although many Ca V channels are modulated by CaM, the N-type channels are probably insensitive to [Ca 2ϩ ] i rises in the range (Ͻ2 M) reachable by release from stores).This receptor specificity parallels stark receptor specificity in the induction of IP 3 -mediated [Ca 2ϩ

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“…Hilgemann and Ball (12) revealed for the first time that the Na ϩ /Ca 2ϩ exchanger and ATP-sensitive K ϩ channels are positively regulated by endogenous PtdIns(4,5)P 2 in guinea pig cardiac cell membranes. Recent studies have demonstrated that PtdIns(4,5)P 2 modulates the function of a number of ion channels, including many inwardly rectifying K ϩ channels (13)(14)(15), the HERG K ϩ channel (16) and voltage-gated P/Q-type Ca 2ϩ channels (17).…”

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confidence: 99%

Regulation of Cardiac IKs Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate

Ding

Toyoda

Matsuura

2004

Journal of Biological Chemistry

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Regulation of the slowly activating component of delayed rectifier K ؉ current (I Ks ) by membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PtdIns-(4,5)P 2 ) was examined in guinea pig atrial myocytes using the whole-cell patch clamp method. I Ks was elicited by depolarizing voltage steps given from a holding potential of ؊50 mV, and the effect of various test reagents on I Ks was assessed by measuring the amplitude of tail current elicited upon return to the holding potential following a 2-s depolarization to ؉30 mV. Intracellular application of 50 M wortmannin through a recording pipette evoked a progressive increase in I Ks over a 10 -15-min period to 208.5 ؎ 14.6% (n ‫؍‬ 9) of initial magnitude obtained shortly after rupture of the patch membrane. Intracellular application of anti-PtdIns(4,5)P 2 monoclonal antibody also increased the amplitude of I Ks to 198.4 ؎ 19.9% (n ‫؍‬ 5). In contrast, intracellular loading with exogenous PtdIns(4,5)P 2 at 10 and 100 M produced a marked decrease in the amplitude of I Ks to 54.3 ؎ 3.8% (n ‫؍‬ 5) and 44.8 ؎ 8.2% (n ‫؍‬ 5), respectively. Intracellular application of neomycin (50 M) or aluminum (50 M) evoked an increase in the amplitude of I Ks to 161.0 ؎ 13.5% (n ‫؍‬ 4) and 150.0 ؎ 8.2% (n ‫؍‬ 4), respectively. These results strongly suggest that I Ks channel is inhibited by endogenous membrane PtdIns(4,5)P 2 through the electrostatic interaction with the negatively charged head group on PtdIns(4,5)P 2 . Potentiation of I Ks by P2Y receptor stimulation with 50 M ATP was almost totally abolished when PtdIns(4,5)P 2 was included in the pipette solution, suggesting that depletion of membrane PtdIns(4,5)P 2 is involved in the potentiation of I Ks by P2Y receptor stimulation. Thus, membrane PtdIns(4,5)P 2 may act as an important physiological regulator of I Ks in guinea pig atrial myocytes.The delayed rectifier K ϩ current (I K ) 1 is activated by membrane depolarization and thereby provides an outward current, which is essential for initiating phase 3 repolarization of the action potential in cardiac muscle. Two kinetically and pharmacologically distinct components of I K , I Kr (rapid) and I Ks (slow), have been identified in cardiac myocytes from various mammalian species (1, 2) including humans (3). The KCNQ1 gene encodes the pore-forming ␣ subunit, K V LQT1, that assembles with an accessory ␤ subunit minK (I sK ) protein (encoded by KCNE1 gene) to produce the I Ks channel (4, 5), whereas the HERG (human ether-á -go-go-related gene) product forms the pore-forming subunit of the I Kr channel (6, 7). Mutations in any of these genes have been linked to long QT syndrome, an inherited cardiac arrhythmia characterized by abnormal ventricular repolarization and a high risk for sudden cardiac death (8).Previous studies have demonstrated that both I Ks and I Kr represent relevant targets for the actions of autonomic neurotransmitters, hormones, intracellular messengers, and exogenous drugs. I Ks is modulated by protein kinase A, protein kinase C (PKC), and intracellular ...

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Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2

Cited by 226 publications

References 29 publications

PIP ₂ controls voltage-sensor movement and pore opening of Kv channels through the S4–S5 linker

PIP ₂ controls voltage-sensor movement and pore opening of Kv channels through the S4–S5 linker

Combined Phosphoinositide and Ca2+ Signals Mediating Receptor Specificity toward Neuronal Ca2+ Channels

Regulation of Cardiac IKs Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate

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Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2

Cited by 226 publications

References 29 publications

PIP 2 controls voltage-sensor movement and pore opening of Kv channels through the S4–S5 linker

PIP 2 controls voltage-sensor movement and pore opening of Kv channels through the S4–S5 linker

Combined Phosphoinositide and Ca2+ Signals Mediating Receptor Specificity toward Neuronal Ca2+ Channels

Regulation of Cardiac IKs Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate

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PIP ₂ controls voltage-sensor movement and pore opening of Kv channels through the S4–S5 linker

PIP ₂ controls voltage-sensor movement and pore opening of Kv channels through the S4–S5 linker