Molecular moieties masking Ca2+-dependent facilitation of voltage-gated Cav2.2 Ca2+ channels
| العنوان: | Molecular moieties masking Ca2+-dependent facilitation of voltage-gated Cav2.2 Ca2+ channels |
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| المؤلفون: | Jessica Thomas, Daniel Soh, Amy S. Lee, Jussara Hagen |
| المصدر: | The Journal of General Physiology |
| بيانات النشر: | The Rockefeller University Press, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Calmodulin, Physiology, Plasma protein binding, Membrane Potentials, 03 medical and health sciences, 0302 clinical medicine, Calcium Channels, N-Type, Animals, Humans, Binding site, Research Articles, Binding Sites, biology, Voltage-gated ion channel, Voltage-dependent calcium channel, Chemistry, Alternative splicing, Rats, Alternative Splicing, 030104 developmental biology, HEK293 Cells, Synaptic plasticity, RNA splicing, Biophysics, biology.protein, Calcium, 030217 neurology & neurosurgery, Research Article, Protein Binding |
| الوصف: | Ca2+-dependent facilitation is a positive feedback mechanism that regulates Cav2.1 P/Q-type channels but not closely related Cav2.2 N-type channels. Thomas et al. identify the molecular determinants that distinguish the ability of Cav2.1 and Cav2.2 to undergo Ca2+-dependent facilitation. Voltage-gated Cav2.1 (P/Q-type) Ca2+ channels undergo Ca2+-dependent inactivation (CDI) and facilitation (CDF), both of which contribute to short-term synaptic plasticity. Both CDI and CDF are mediated by calmodulin (CaM) binding to sites in the C-terminal domain of the Cav2.1 α1 subunit, most notably to a consensus CaM-binding IQ-like (IQ) domain. Closely related Cav2.2 (N-type) channels display CDI but not CDF, despite overall conservation of the IQ and additional sites (pre-IQ, EF-hand–like [EF] domain, and CaM-binding domain) that regulate CDF of Cav2.1. Here we investigate the molecular determinants that prevent Cav2.2 channels from undergoing CDF. Although alternative splicing of C-terminal exons regulates CDF of Cav2.1, the splicing of analogous exons in Cav2.2 does not reveal CDF. Transfer of sequences encoding the Cav2.1 EF, pre-IQ, and IQ together (EF-pre-IQ-IQ), but not individually, are sufficient to support CDF in chimeric Cav2.2 channels; Cav2.1 chimeras containing the corresponding domains of Cav2.2, either alone or together, fail to undergo CDF. In contrast to the weak binding of CaM to just the pre-IQ and IQ of Cav2.2, CaM binds to the EF-pre-IQ-IQ of Cav2.2 as well as to the corresponding domains of Cav2.1. Therefore, the lack of CDF in Cav2.2 likely arises from an inability of its EF-pre-IQ-IQ to transduce the effects of CaM rather than weak binding to CaM per se. Our results reveal a functional divergence in the CDF regulatory domains of Cav2 channels, which may help to diversify the modes by which Cav2.1 and Cav2.2 can modify synaptic transmission. |
| اللغة: | English |
| تدمد: | 1540-7748 0022-1295 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9c2dff46cd5f9906d4e59f7c7be01294Test http://europepmc.org/articles/PMC5749111Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9c2dff46cd5f9906d4e59f7c7be01294 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15407748 00221295 |
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