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Inactivation influences the extent of inhibition of voltage-gated Ca(+2) channels by Gem—implications for channelopathies

Voltage-gated Ca(2+) channels (VGCC) directly control muscle contraction and neurotransmitter release, and slower processes such as cell differentiation, migration, and death. They are potently inhibited by RGK GTP-ases (Rem, Rem2, Rad, and Gem/Kir), which decrease Ca(2+) channel membrane expression...

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Autores principales: Allam, Salma, Levenson-Palmer, Rose, Chia Chang, Zuleen, Kaur, Sukhjinder, Cernuda, Bryan, Raman, Ananya, Booth, Audrey, Dobbins, Scott, Suppa, Gabrielle, Yang, Jian, Buraei, Zafir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10466392/
https://www.ncbi.nlm.nih.gov/pubmed/37654674
http://dx.doi.org/10.3389/fphys.2023.1155976
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author Allam, Salma
Levenson-Palmer, Rose
Chia Chang, Zuleen
Kaur, Sukhjinder
Cernuda, Bryan
Raman, Ananya
Booth, Audrey
Dobbins, Scott
Suppa, Gabrielle
Yang, Jian
Buraei, Zafir
author_facet Allam, Salma
Levenson-Palmer, Rose
Chia Chang, Zuleen
Kaur, Sukhjinder
Cernuda, Bryan
Raman, Ananya
Booth, Audrey
Dobbins, Scott
Suppa, Gabrielle
Yang, Jian
Buraei, Zafir
author_sort Allam, Salma
collection PubMed
description Voltage-gated Ca(2+) channels (VGCC) directly control muscle contraction and neurotransmitter release, and slower processes such as cell differentiation, migration, and death. They are potently inhibited by RGK GTP-ases (Rem, Rem2, Rad, and Gem/Kir), which decrease Ca(2+) channel membrane expression, as well as directly inhibit membrane-resident channels. The mechanisms of membrane-resident channel inhibition are difficult to study because RGK-overexpression causes complete or near complete channel inhibition. Using titrated levels of Gem expression in Xenopus oocytes to inhibit WT P/Q-type calcium channels by ∼50%, we show that inhibition is dependent on channel inactivation. Interestingly, fast-inactivating channels, including Familial Hemiplegic Migraine mutants, are more potently inhibited than WT channels, while slow-inactivating channels, such as those expressed with the Cavβ(2a) auxiliary subunit, are spared. We found similar results in L-type channels, and, remarkably, Timothy Syndrome mutant channels were insensitive to Gem inhibition. Further results suggest that RGKs slow channel recovery from inactivation and further implicate RGKs as likely modulating factors in channelopathies.
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spelling pubmed-104663922023-08-31 Inactivation influences the extent of inhibition of voltage-gated Ca(+2) channels by Gem—implications for channelopathies Allam, Salma Levenson-Palmer, Rose Chia Chang, Zuleen Kaur, Sukhjinder Cernuda, Bryan Raman, Ananya Booth, Audrey Dobbins, Scott Suppa, Gabrielle Yang, Jian Buraei, Zafir Front Physiol Physiology Voltage-gated Ca(2+) channels (VGCC) directly control muscle contraction and neurotransmitter release, and slower processes such as cell differentiation, migration, and death. They are potently inhibited by RGK GTP-ases (Rem, Rem2, Rad, and Gem/Kir), which decrease Ca(2+) channel membrane expression, as well as directly inhibit membrane-resident channels. The mechanisms of membrane-resident channel inhibition are difficult to study because RGK-overexpression causes complete or near complete channel inhibition. Using titrated levels of Gem expression in Xenopus oocytes to inhibit WT P/Q-type calcium channels by ∼50%, we show that inhibition is dependent on channel inactivation. Interestingly, fast-inactivating channels, including Familial Hemiplegic Migraine mutants, are more potently inhibited than WT channels, while slow-inactivating channels, such as those expressed with the Cavβ(2a) auxiliary subunit, are spared. We found similar results in L-type channels, and, remarkably, Timothy Syndrome mutant channels were insensitive to Gem inhibition. Further results suggest that RGKs slow channel recovery from inactivation and further implicate RGKs as likely modulating factors in channelopathies. Frontiers Media S.A. 2023-08-16 /pmc/articles/PMC10466392/ /pubmed/37654674 http://dx.doi.org/10.3389/fphys.2023.1155976 Text en Copyright © 2023 Allam, Levenson-Palmer, Chia Chang, Kaur, Cernuda, Raman, Booth, Dobbins, Suppa, Yang and Buraei. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Allam, Salma
Levenson-Palmer, Rose
Chia Chang, Zuleen
Kaur, Sukhjinder
Cernuda, Bryan
Raman, Ananya
Booth, Audrey
Dobbins, Scott
Suppa, Gabrielle
Yang, Jian
Buraei, Zafir
Inactivation influences the extent of inhibition of voltage-gated Ca(+2) channels by Gem—implications for channelopathies
title Inactivation influences the extent of inhibition of voltage-gated Ca(+2) channels by Gem—implications for channelopathies
title_full Inactivation influences the extent of inhibition of voltage-gated Ca(+2) channels by Gem—implications for channelopathies
title_fullStr Inactivation influences the extent of inhibition of voltage-gated Ca(+2) channels by Gem—implications for channelopathies
title_full_unstemmed Inactivation influences the extent of inhibition of voltage-gated Ca(+2) channels by Gem—implications for channelopathies
title_short Inactivation influences the extent of inhibition of voltage-gated Ca(+2) channels by Gem—implications for channelopathies
title_sort inactivation influences the extent of inhibition of voltage-gated ca(+2) channels by gem—implications for channelopathies
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10466392/
https://www.ncbi.nlm.nih.gov/pubmed/37654674
http://dx.doi.org/10.3389/fphys.2023.1155976
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