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Calmodulin limits pathogenic Na+ channel persistent current.

TitleCalmodulin limits pathogenic Na+ channel persistent current.
Publication TypeJournal Article
Year of Publication2017
AuthorsYan H, Wang C, Marx SO, Pitt GS
JournalJ Gen Physiol
Date Published2017 Feb

Increased "persistent" current, caused by delayed inactivation, through voltage-gated Na(+) (NaV) channels leads to cardiac arrhythmias or epilepsy. The underlying molecular contributors to these inactivation defects are poorly understood. Here, we show that calmodulin (CaM) binding to multiple sites within NaV channel intracellular C-terminal domains (CTDs) limits persistent Na(+) current and accelerates inactivation across the NaV family. Arrhythmia or epilepsy mutations located in NaV1.5 or NaV1.2 channel CTDs, respectively, reduce CaM binding either directly or by interfering with CTD-CTD interchannel interactions. Boosting the availability of CaM, thus shifting its binding equilibrium, restores wild-type (WT)-like inactivation in mutant NaV1.5 and NaV1.2 channels and likewise diminishes the comparatively large persistent Na(+) current through WT NaV1.6, whose CTD displays relatively low CaM affinity. In cerebellar Purkinje neurons, in which NaV1.6 promotes a large physiological persistent Na(+) current, increased CaM diminishes the persistent Na(+) current, suggesting that the endogenous, comparatively weak affinity of NaV1.6 for apoCaM is important for physiological persistent current.

Alternate JournalJ. Gen. Physiol.
PubMed ID28087622
PubMed Central IDPMC5299624
Grant ListR01 HL112918 / HL / NHLBI NIH HHS / United States
R01 HL122967 / HL / NHLBI NIH HHS / United States