Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels

Niu, Jacqueline; Dick, Ivy E.; Yang, Wanjun; Bamgboye, Moradeke A.; Yue, David T.; Tomaselli, Gordon F.; Inoue, Takanari; Ben-Johny, Manu

doi:10.7554/elife.35222

Cited by 32 publications

(55 citation statements)

References 120 publications

(211 reference statements)

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“…Interestingly, STAC proteins have recently been found to engage Ca V s (51)(52)(53)(54)(55)(56)(57) and were shown to interact with the EF-hand domain, abolishing CDI (26). This is reminiscent of the effect of FHFs on Na V s, and it was shown that FHFs can abolish CDI in Na V 1.4 (26). Although there are parallels between Na V and Ca V channels in regard to CaM regulation, there is also divergence.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, FHFs have been shown to abolish CDI in Na V 1.4 (26), an effect that may be ascribed to its inherent effect on the EF-hand orientation, locking it into a position such that no Ca 2+ -dependent conformational change occurs. Similarly, STAC proteins, which can bind to two different regions in Ca V 1 channels (26,(51)(52)(53)(54)(55)(56), including the EFhand domain (26), could affect the relative orientation between EF-hand and IQ domain. How this conformational change further results in inactivation remains to be shown, but of note is the ability of the EF-hand domain to interact with the III-IV linker, and that this interaction affects channel inactivation (14).…”

Section: Discussionmentioning

confidence: 99%

“…Despite these parallels, there is also divergence, as Na V CT fragments bind Ca 2+ -free CaM stronger than Ca 2+ /CaM, opposite to most Ca V 1 and Ca V 2 channels. In addition, Na V CT fragments can bind FHF proteins, whereas Ca V CTs do not (13,25,26). CaM has also been reported to interact with the III-IV linker in Na V 1.5 (16,27), but so far this has not yet been described for Ca V s.…”

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confidence: 97%

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Crystal structures of Ca ²⁺ –calmodulin bound to Na _V C-terminal regions suggest role for EF-hand domain in binding and inactivation

Gardill

Rivera-Acevedo

Tung

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Voltage-gated sodium (Na V ) and calcium channels (Ca V ) form targets for calmodulin (CaM), which affects channel inactivation properties. A major interaction site for CaM resides in the Cterminal (CT) region, consisting of an IQ domain downstream of an EF-hand domain. We present a crystal structure of fully Ca 2+occupied CaM, bound to the CT of Na V 1.5. The structure shows that the C-terminal lobe binds to a site ∼90°rotated relative to a previous site reported for an apoCaM complex with the Na V 1.5 CT and for ternary complexes containing fibroblast growth factor homologous factors (FHF). We show that the binding of FHFs forces the EF-hand domain in a conformation that does not allow binding of the Ca 2+ -occupied C-lobe of CaM. These observations highlight the central role of the EF-hand domain in modulating the binding mode of CaM. The binding sites for Ca 2+ -free and Ca 2+ -occupied CaM contain targets for mutations linked to long-QT syndrome, a type of inherited arrhythmia. The related Na V 1.4 channel has been shown to undergo Ca 2+ -dependent inactivation (CDI) akin to Ca V s. We present a crystal structure of Ca 2+ /CaM bound to the Na V 1.4 IQ domain, which shows a binding mode that would clash with the EF-hand domain. We postulate the relative reorientation of the EFhand domain and the IQ domain as a possible conformational switch that underlies CDI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

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Crystal structures of Ca ²⁺ –calmodulin bound to Na _V C-terminal regions suggest role for EF-hand domain in binding and inactivation

Gardill

Rivera-Acevedo

Tung

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…We hypothesize that the calcium-binding protein calmodulin (CaM) is a yet-unknown N-terminal interaction partner. CaM is well-known to regulate voltage-gated sodium (Na v ) and calcium (Ca v ) channel functions 2,14 . Its interaction with Na v and Ca v C-terminal domains (CTD) is especially well established 2,15 .…”

Section: Introductionmentioning

confidence: 99%

Calmodulin binds to the N-terminal domain of the cardiac sodium channel Na_v1.5

Wang

Vermij

Sottas

et al. 2020

Preprint

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1The cardiac voltage-gated sodium channel Nav1.5 conducts the rapid inward sodium current crucial for 2 cardiomyocyte excitability. Loss-of-function mutations in its gene SCN5A are linked to cardiac arrhythmias 3 such as Brugada Syndrome (BrS). Several BrS-associated mutations in the Nav1.5 N-terminal domain exert 4 a dominant-negative effect (DNE) on wild-type channel function, for which mechanisms remain poorly 5 understood. We aim to contribute to the understanding of BrS pathophysiology by characterizing three 6 mutations in the Nav1.5 N-terminal domain (NTD): Y87C-here newly identified-, R104W and R121W. In 7 addition, we hypothesize that the calcium sensor protein calmodulin is a new NTD binding partner. 8Recordings of whole-cell sodium currents in TsA-201 cells expressing WT and variant Nav1.5 showed that 9 Y87C and R104W but not R121W exert a DNE on WT channels. Biotinylation assays revealed reduction 10 in fully glycosylated Nav1.5 at the cell surface and in whole-cell lysates. Localization of Nav1.5 WT channel 11 with the ER however did not change in the presence of variants, shown by transfected and stained rat 12 neonatal cardiomyocytes. We next demonstrated that calmodulin binds Nav1.5 N-terminus using in silico 13 modeling, SPOTS, pull-down and proximity ligation assays. This binding is impaired in the R121W variant 14 and in a Nav1.5 construct missing residues 80-105, a predicted calmodulin binding site. 15In conclusion, we present the first evidence that calmodulin binds to the Nav1.5 NTD, which seems to be a 16 determinant for the DNE. 17Wang et al.3

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“…Larger calcium currents may be the result of changes in voltage-dependent activation and inactivation curves of the channels to more hyperpolarized potentials, as identified in humans presenting different neurological disorders with a common expression of spasticity (57)(58)(59) or alterated upstream regulatory elements of the channels (26). Moreover, Ca V 1.3 calcium channels may increase neuronal excitabil-ity after injury indirectly, by cooperative gaiting of clustered Ca V 1.3 channels (60), activating calcium activated nonspecific cation channels (16) and BK channels (61) or promoting activation of calmodulin or calcium-dependent calpains to increase sodium channels activity after SCI (62,63). In our study nimodipine treatment does not completely block the sustained motor contraction in the chronic un-treated animals indicating that other cellular mechanisms than Ca V 1.3 channels support the the expression of spasticity.…”

Section: Discussionmentioning

confidence: 99%

Nimodipine prevents the development of spasticity after spinal cord injury

Marcantoni

Fuchs

Lőw

et al. 2019

Preprint

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Spasticity, one of the most frequent comorbidities of spinal cord injury (SCI), disrupts motor recovery and quality of life. Despite major progress in neurorehabilitative and pharmacological approaches, no curative treatment for spasticity exists. Here, we show in a mouse model of chronic SCI that treatment with nimodipine -an FDA-approved L-type calcium channel blocker -starting in the acute phase of SCI completely prevents the development of spasticity measured as increased muscle tone and spontaneous spasms. The aberrant muscle activities are permanently blocked even after termination of the treatment. Constitutive and conditional silencing in neuronal subtypes of Ca V 1.3 channels shows that preventive effect of nimodipine on spasticity after SCI is mediated by the neuronal Ca V 1.3 channels. This study identifies a potentially curative treatment protocol with a specific target for the prevention of spasticity after SCI.

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Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels

Cited by 32 publications

References 120 publications

Crystal structures of Ca ²⁺ –calmodulin bound to Na _V C-terminal regions suggest role for EF-hand domain in binding and inactivation

Crystal structures of Ca ²⁺ –calmodulin bound to Na _V C-terminal regions suggest role for EF-hand domain in binding and inactivation

Calmodulin binds to the N-terminal domain of the cardiac sodium channel Na_v1.5

Nimodipine prevents the development of spasticity after spinal cord injury

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Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels

Cited by 32 publications

References 120 publications

Crystal structures of Ca 2+ –calmodulin bound to Na V C-terminal regions suggest role for EF-hand domain in binding and inactivation

Crystal structures of Ca 2+ –calmodulin bound to Na V C-terminal regions suggest role for EF-hand domain in binding and inactivation

Calmodulin binds to the N-terminal domain of the cardiac sodium channel Nav1.5

Nimodipine prevents the development of spasticity after spinal cord injury

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Crystal structures of Ca ²⁺ –calmodulin bound to Na _V C-terminal regions suggest role for EF-hand domain in binding and inactivation

Crystal structures of Ca ²⁺ –calmodulin bound to Na _V C-terminal regions suggest role for EF-hand domain in binding and inactivation

Calmodulin binds to the N-terminal domain of the cardiac sodium channel Na_v1.5