Calmodulin-Connexin Partnership in Gap Junction Channel Regulation-Calmodulin-Cork Gating Model
In the past four decades numerous findings have indicated that gap junction channel gating is mediated by intracellular calcium concentrations ([Ca<sup>2+</sup><sub>i</sub>]) in the high nanomolar range via calmodulin (CaM). We have proposed a CaM-based gating model based on...
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MDPI AG
2021-12-01
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author | Camillo Peracchia Lillian Mae Leverone Peracchia |
author_facet | Camillo Peracchia Lillian Mae Leverone Peracchia |
author_sort | Camillo Peracchia |
collection | DOAJ |
description | In the past four decades numerous findings have indicated that gap junction channel gating is mediated by intracellular calcium concentrations ([Ca<sup>2+</sup><sub>i</sub>]) in the high nanomolar range via calmodulin (CaM). We have proposed a CaM-based gating model based on evidence for a direct CaM role in gating. This model is based on the following: CaM inhibitors and the inhibition of CaM expression to prevent chemical gating. A CaM mutant with higher Ca<sup>2+</sup> sensitivity greatly increases gating sensitivity. CaM co-localizes with connexins. Connexins have high-affinity CaM-binding sites. Connexin mutants paired to wild type connexins have a higher gating sensitivity, which is eliminated by the inhibition of CaM expression. Repeated trans-junctional voltage (Vj) pulses progressively close channels by the chemical/slow gate (CaM’s N-lobe). At the single channel level, the gate closes and opens slowly with on-off fluctuations. Internally perfused crayfish axons lose gating competency but recover it by the addition of Ca-CaM to the internal perfusion solution. X-ray diffraction data demonstrate that isolated gap junctions are gated at the cytoplasmic end by a particle of the size of a CaM lobe. We have proposed two types of CaM-driven gating: “Ca-CaM-Cork” and “CaM-Cork”. In the first, the gating involves Ca<sup>2+</sup>-induced CaM activation. In the second, the gating occurs without a [Ca<sup>2+</sup>]<sub>i</sub> rise. |
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language | English |
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spelling | doaj.art-9e087ab99a474771b650a856ec37845d2023-11-23T02:32:27ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0122231305510.3390/ijms222313055Calmodulin-Connexin Partnership in Gap Junction Channel Regulation-Calmodulin-Cork Gating ModelCamillo Peracchia0Lillian Mae Leverone Peracchia1Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USADepartment of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USAIn the past four decades numerous findings have indicated that gap junction channel gating is mediated by intracellular calcium concentrations ([Ca<sup>2+</sup><sub>i</sub>]) in the high nanomolar range via calmodulin (CaM). We have proposed a CaM-based gating model based on evidence for a direct CaM role in gating. This model is based on the following: CaM inhibitors and the inhibition of CaM expression to prevent chemical gating. A CaM mutant with higher Ca<sup>2+</sup> sensitivity greatly increases gating sensitivity. CaM co-localizes with connexins. Connexins have high-affinity CaM-binding sites. Connexin mutants paired to wild type connexins have a higher gating sensitivity, which is eliminated by the inhibition of CaM expression. Repeated trans-junctional voltage (Vj) pulses progressively close channels by the chemical/slow gate (CaM’s N-lobe). At the single channel level, the gate closes and opens slowly with on-off fluctuations. Internally perfused crayfish axons lose gating competency but recover it by the addition of Ca-CaM to the internal perfusion solution. X-ray diffraction data demonstrate that isolated gap junctions are gated at the cytoplasmic end by a particle of the size of a CaM lobe. We have proposed two types of CaM-driven gating: “Ca-CaM-Cork” and “CaM-Cork”. In the first, the gating involves Ca<sup>2+</sup>-induced CaM activation. In the second, the gating occurs without a [Ca<sup>2+</sup>]<sub>i</sub> rise.https://www.mdpi.com/1422-0067/22/23/13055gap junctionsconnexinsinnexinschannel gatingcalciumcalmodulin |
spellingShingle | Camillo Peracchia Lillian Mae Leverone Peracchia Calmodulin-Connexin Partnership in Gap Junction Channel Regulation-Calmodulin-Cork Gating Model International Journal of Molecular Sciences gap junctions connexins innexins channel gating calcium calmodulin |
title | Calmodulin-Connexin Partnership in Gap Junction Channel Regulation-Calmodulin-Cork Gating Model |
title_full | Calmodulin-Connexin Partnership in Gap Junction Channel Regulation-Calmodulin-Cork Gating Model |
title_fullStr | Calmodulin-Connexin Partnership in Gap Junction Channel Regulation-Calmodulin-Cork Gating Model |
title_full_unstemmed | Calmodulin-Connexin Partnership in Gap Junction Channel Regulation-Calmodulin-Cork Gating Model |
title_short | Calmodulin-Connexin Partnership in Gap Junction Channel Regulation-Calmodulin-Cork Gating Model |
title_sort | calmodulin connexin partnership in gap junction channel regulation calmodulin cork gating model |
topic | gap junctions connexins innexins channel gating calcium calmodulin |
url | https://www.mdpi.com/1422-0067/22/23/13055 |
work_keys_str_mv | AT camilloperacchia calmodulinconnexinpartnershipingapjunctionchannelregulationcalmodulincorkgatingmodel AT lillianmaeleveroneperacchia calmodulinconnexinpartnershipingapjunctionchannelregulationcalmodulincorkgatingmodel |