Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels
Calmodulin (CaM) serves as a pervasive regulatory subunit of CaV1, CaV2, and NaV1 channels, exploiting a functionally conserved carboxy-tail element to afford dynamic Ca2+-feedback of cellular excitability in neurons and cardiomyocytes. Yet this modularity counters functional adaptability, as global...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2018-09-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/35222 |
| _version_ | 1828384325284921344 |
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| author | Jacqueline Niu Ivy E Dick Wanjun Yang Moradeke A Bamgboye David T Yue Gordon Tomaselli Takanari Inoue Manu Ben-Johny |
| author_facet | Jacqueline Niu Ivy E Dick Wanjun Yang Moradeke A Bamgboye David T Yue Gordon Tomaselli Takanari Inoue Manu Ben-Johny |
| author_sort | Jacqueline Niu |
| collection | DOAJ |
| description | Calmodulin (CaM) serves as a pervasive regulatory subunit of CaV1, CaV2, and NaV1 channels, exploiting a functionally conserved carboxy-tail element to afford dynamic Ca2+-feedback of cellular excitability in neurons and cardiomyocytes. Yet this modularity counters functional adaptability, as global changes in ambient CaM indiscriminately alter its targets. Here, we demonstrate that two structurally unrelated proteins, SH3 and cysteine-rich domain (stac) and fibroblast growth factor homologous factors (fhf) selectively diminish Ca2+/CaM-regulation of CaV1 and NaV1 families, respectively. The two proteins operate on allosteric sites within upstream portions of respective channel carboxy-tails, distinct from the CaM-binding interface. Generalizing this mechanism, insertion of a short RxxK binding motif into CaV1.3 carboxy-tail confers synthetic switching of CaM regulation by Mona SH3 domain. Overall, our findings identify a general class of auxiliary proteins that modify Ca2+/CaM signaling to individual targets allowing spatial and temporal orchestration of feedback, and outline strategies for engineering Ca2+/CaM signaling to individual targets. |
| first_indexed | 2024-12-10T05:02:04Z |
| format | Article |
| id | doaj.art-9b0826e54a884045983cc706ec028cd5 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T05:02:04Z |
| publishDate | 2018-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-9b0826e54a884045983cc706ec028cd52022-12-22T02:01:23ZengeLife Sciences Publications LtdeLife2050-084X2018-09-01710.7554/eLife.35222Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channelsJacqueline Niu0Ivy E Dick1Wanjun Yang2Moradeke A Bamgboye3David T Yue4Gordon Tomaselli5Takanari Inoue6Manu Ben-Johny7https://orcid.org/0000-0002-5645-0815Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United StatesDepartment of Physiology, University of Maryland, Baltimore, United StatesDepartment of Cardiology, Johns Hopkins University, Baltimore, United StatesDepartment of Physiology, University of Maryland, Baltimore, United StatesDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, United StatesDepartment of Cardiology, Johns Hopkins University, Baltimore, United StatesDepartment of Cell Biology, Johns Hopkins University, Baltimore, United States; Center for Cell Dynamics, Institute for Basic Biomedical Sciences, Johns Hopkins University, Baltimore, United StatesDepartment of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, United StatesCalmodulin (CaM) serves as a pervasive regulatory subunit of CaV1, CaV2, and NaV1 channels, exploiting a functionally conserved carboxy-tail element to afford dynamic Ca2+-feedback of cellular excitability in neurons and cardiomyocytes. Yet this modularity counters functional adaptability, as global changes in ambient CaM indiscriminately alter its targets. Here, we demonstrate that two structurally unrelated proteins, SH3 and cysteine-rich domain (stac) and fibroblast growth factor homologous factors (fhf) selectively diminish Ca2+/CaM-regulation of CaV1 and NaV1 families, respectively. The two proteins operate on allosteric sites within upstream portions of respective channel carboxy-tails, distinct from the CaM-binding interface. Generalizing this mechanism, insertion of a short RxxK binding motif into CaV1.3 carboxy-tail confers synthetic switching of CaM regulation by Mona SH3 domain. Overall, our findings identify a general class of auxiliary proteins that modify Ca2+/CaM signaling to individual targets allowing spatial and temporal orchestration of feedback, and outline strategies for engineering Ca2+/CaM signaling to individual targets.https://elifesciences.org/articles/35222Ca channelsNa channelscalmodulinfibroblast growth factor homologous factorsSH3 and cysteine rich domain proteinscalcium regulation |
| spellingShingle | Jacqueline Niu Ivy E Dick Wanjun Yang Moradeke A Bamgboye David T Yue Gordon Tomaselli Takanari Inoue Manu Ben-Johny Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels eLife Ca channels Na channels calmodulin fibroblast growth factor homologous factors SH3 and cysteine rich domain proteins calcium regulation |
| title | Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels |
| title_full | Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels |
| title_fullStr | Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels |
| title_full_unstemmed | Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels |
| title_short | Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels |
| title_sort | allosteric regulators selectively prevent ca2 feedback of cav and nav channels |
| topic | Ca channels Na channels calmodulin fibroblast growth factor homologous factors SH3 and cysteine rich domain proteins calcium regulation |
| url | https://elifesciences.org/articles/35222 |
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