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Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin
Ca(2+) channels and calmodulin are two prominent signaling hubs(1) that synergistically impact functions as diverse as cardiac excitability(2), synaptic plasticity(3), and gene transcription(4). It is thereby fitting that these hubs are in some sense coordinated, as the opening of Ca(V)1-2 Ca(2+) ch...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553577/ https://www.ncbi.nlm.nih.gov/pubmed/20139964 http://dx.doi.org/10.1038/nature08766 |
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author | Liu, Xiaodong Yang, Philemon S. Yang, Wanjun Yue, David T. |
author_facet | Liu, Xiaodong Yang, Philemon S. Yang, Wanjun Yue, David T. |
author_sort | Liu, Xiaodong |
collection | PubMed |
description | Ca(2+) channels and calmodulin are two prominent signaling hubs(1) that synergistically impact functions as diverse as cardiac excitability(2), synaptic plasticity(3), and gene transcription(4). It is thereby fitting that these hubs are in some sense coordinated, as the opening of Ca(V)1-2 Ca(2+) channels are regulated by a single calmodulin (CaM) constitutively complexed with channels(5). The Ca(2+)-free form of CaM (apoCaM) is already preassociated with the IQ domain on the channel carboxy terminus, and subsequent Ca(2+) binding to this ‘resident’ CaM drives conformational changes that then trigger regulation of channel opening(6). Another potential avenue for channel-CaM coordination could arise from the absence of Ca(2+) regulation in channels lacking a preassociated CaM(6,7). Natural fluctuations in CaM levels might then influence the fraction of regulatable channels, and thereby the overall strength of Ca(2+) feedback. However, the prevailing view has been that the ultra-strong affinity of channels for apoCaM ensures their saturation with CaM(8), yielding a significant form of concentration independence between Ca(2+) channels and CaM. Here, we reveal significant exceptions to this autonomy, by combining electrophysiology to characterize channel regulation, with optical FRET sensor determination of free apoCaM concentration in live cells(9). This approach translates quantitative CaM biochemistry from the traditional test-tube context, into the realm of functioning holochannels within intact cells. From this perspective, we find that long splice forms of Ca(V)1.3 and Ca(V)1.4 channels include a distal carboxy tail(10-12) that resembles an enzyme competitive inhibitor, which retunes channel affinity for apoCaM so that natural CaM variations affect the strength of Ca(2+) feedback modulation. Given the ubiquity of these channels(13,14), the connection between ambient CaM levels and Ca(2+) entry via channels is broadly significant for Ca(2+) homeostasis. Strategies like ours promise key advances for the in situ analysis of signaling molecules resistant to in vitro reconstitution, such as Ca(2+) channels. |
format | Online Article Text |
id | pubmed-3553577 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
record_format | MEDLINE/PubMed |
spelling | pubmed-35535772013-01-24 Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin Liu, Xiaodong Yang, Philemon S. Yang, Wanjun Yue, David T. Nature Article Ca(2+) channels and calmodulin are two prominent signaling hubs(1) that synergistically impact functions as diverse as cardiac excitability(2), synaptic plasticity(3), and gene transcription(4). It is thereby fitting that these hubs are in some sense coordinated, as the opening of Ca(V)1-2 Ca(2+) channels are regulated by a single calmodulin (CaM) constitutively complexed with channels(5). The Ca(2+)-free form of CaM (apoCaM) is already preassociated with the IQ domain on the channel carboxy terminus, and subsequent Ca(2+) binding to this ‘resident’ CaM drives conformational changes that then trigger regulation of channel opening(6). Another potential avenue for channel-CaM coordination could arise from the absence of Ca(2+) regulation in channels lacking a preassociated CaM(6,7). Natural fluctuations in CaM levels might then influence the fraction of regulatable channels, and thereby the overall strength of Ca(2+) feedback. However, the prevailing view has been that the ultra-strong affinity of channels for apoCaM ensures their saturation with CaM(8), yielding a significant form of concentration independence between Ca(2+) channels and CaM. Here, we reveal significant exceptions to this autonomy, by combining electrophysiology to characterize channel regulation, with optical FRET sensor determination of free apoCaM concentration in live cells(9). This approach translates quantitative CaM biochemistry from the traditional test-tube context, into the realm of functioning holochannels within intact cells. From this perspective, we find that long splice forms of Ca(V)1.3 and Ca(V)1.4 channels include a distal carboxy tail(10-12) that resembles an enzyme competitive inhibitor, which retunes channel affinity for apoCaM so that natural CaM variations affect the strength of Ca(2+) feedback modulation. Given the ubiquity of these channels(13,14), the connection between ambient CaM levels and Ca(2+) entry via channels is broadly significant for Ca(2+) homeostasis. Strategies like ours promise key advances for the in situ analysis of signaling molecules resistant to in vitro reconstitution, such as Ca(2+) channels. 2010-02-07 2010-02-18 /pmc/articles/PMC3553577/ /pubmed/20139964 http://dx.doi.org/10.1038/nature08766 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Liu, Xiaodong Yang, Philemon S. Yang, Wanjun Yue, David T. Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin |
title | Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin |
title_full | Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin |
title_fullStr | Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin |
title_full_unstemmed | Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin |
title_short | Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin |
title_sort | enzyme-inhibitor-like tuning of ca(2+) channel connectivity with calmodulin |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553577/ https://www.ncbi.nlm.nih.gov/pubmed/20139964 http://dx.doi.org/10.1038/nature08766 |
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