PKC regulation of ion channels: The involvement of PIP2

Gada, Kirin; Logothetis, Diomedes E.

doi:10.1016/j.jbc.2022.102035

Cited by 34 publications

(21 citation statements)

References 172 publications

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“…Although it accounts for less than 1% of the total phospholipids in the plasma membrane, it is a principal signaling molecule and an essential cofactor for ion channel function ( Hansen, 2015 ; Suh and Hille, 2008 ). PIP 2 binds to ion channels directly and modulates their function by facilitating channel opening, preventing current rundown/desensitization, or inhibiting channel activity ( Gada and Logothetis, 2022 ; Suh and Hille, 2008 ). At least 10 different ion channel families are dependent on PIP 2 for their activity ( Gada and Logothetis, 2022 ; Suh and Hille, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

“…PIP 2 binds to ion channels directly and modulates their function by facilitating channel opening, preventing current rundown/desensitization, or inhibiting channel activity ( Gada and Logothetis, 2022 ; Suh and Hille, 2008 ). At least 10 different ion channel families are dependent on PIP 2 for their activity ( Gada and Logothetis, 2022 ; Suh and Hille, 2008 ). A handful of ion channles are negatively regulated by PIP 2 ( Gada and Logothetis, 2022 ; Suh and Hille, 2008 ), one of which is TMEM16B− the only chloride channel that is reported to be inhibited in the presence of PIP 2 to this date ( Ta et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…At least 10 different ion channel families are dependent on PIP 2 for their activity ( Gada and Logothetis, 2022 ; Suh and Hille, 2008 ). A handful of ion channles are negatively regulated by PIP 2 ( Gada and Logothetis, 2022 ; Suh and Hille, 2008 ), one of which is TMEM16B− the only chloride channel that is reported to be inhibited in the presence of PIP 2 to this date ( Ta et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the proton-activated chloride channel PAC by PIP2

Mihaljević

Ruan

Osei-Owusu

et al. 2023

eLife

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Proton-Activated Chloride (PAC) channel is a ubiquitously expressed pH-sensing ion channel, encoded by PACC1 (TMEM206). PAC regulates endosomal acidification and macropinosome shrinkage by releasing chloride from the organelle lumens. It is also found at the cell surface, where it is activated under pathological conditions related to acidosis and contributes to acid-induced cell death. However, the pharmacology of the PAC channel is poorly understood. Here, we report that phosphatidylinositol (4,5)-bisphosphate (PIP2) potently inhibits PAC channel activity. We solved the cryo-electron microscopy structure of PAC with PIP2 at pH 4.0 and identified its putative binding site, which, surprisingly, locates on the extracellular side of the transmembrane domain (TMD). While the overall conformation resembles the previously resolved PAC structure in the desensitized state, the TMD undergoes remodeling upon PIP2-binding. Structural and electrophysiological analyses suggest that PIP2 inhibits the PAC channel by stabilizing the channel in a desensitized-like conformation. Our findings identify PIP2 as a new pharmacological tool for the PAC channel and lay the foundation for future drug discovery targeting this channel.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of the proton-activated chloride channel PAC by PIP2

Mihaljević

Ruan

Osei-Owusu

et al. 2023

eLife

View full text Add to dashboard Cite

show abstract

“…Although it accounts for less than 1% of the total phospholipids in the plasma membrane, it is a principal signaling molecule and an essential cofactor for ion channel function (Hansen, 2015; Suh & Hille, 2008). PIP 2 binds to ion channels directly and modulates their function by facilitating channel opening, preventing current rundown/desensitization, or inhibiting channel activity (Gada & Logothetis, 2022; Suh & Hille, 2008). At least ten different ion channel families are dependent on PIP 2 for their activity, of which only one chloride channel family, TMEM16A, is known to require PIP 2 for channel opening.…”

Section: Introductionmentioning

confidence: 99%

“…At least ten different ion channel families are dependent on PIP 2 for their activity, of which only one chloride channel family, TMEM16A, is known to require PIP 2 for channel opening. Additionally, a handful of ion channels are reported to be inhibited by PIP 2 (Gada & Logothetis, 2022; Suh & Hille, 2008).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the proton-activated chloride channel PAC by PIP₂

Mihaljević

Ruan

Osei-Owusu

et al. 2022

Preprint

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Proton-Activated Chloride (PAC) channel is a ubiquitously expressed pH-sensing ion channel that regulates endosomal acidification and macropinosome shrinkage by releasing chloride from the organelle lumens. It is also found at the cell surface, where it is activated under pathological conditions related to acidosis and contributes to acid-induced cell death. However, the pharmacology of the PAC channel is poorly understood. Here, we report that phosphatidylinositol (4,5)-bisphosphate (PIP2) potently inhibits PAC channel activity. We solved the cryo-electron microscopy structure of PAC with PIP2 at pH 4.0 and identified its binding site, which, surprisingly, locates on the extracellular side of the transmembrane domain (TMD). While the overall conformation resembles the previously resolved PAC structure in the desensitized state, the TMD undergoes remodeling upon PIP2-binding. Structural and electrophysiological analyses suggest that PIP2 inhibits the PAC channel by stabilizing the channel in a desensitized-like conformation. To our knowledge, PAC is the first chloride channel reported to be inhibited by PIP2. Our findings identify PIP2 as a new pharmacological tool for the PAC channel and lay the foundation for future drug discovery targeting this channel.

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