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Cardiovasc Res. 2016 May 15;110(2):279-90. doi: 10.1093/cvr/cvw009. Epub 2016 Jan 19.

Nav1.5 N-terminal domain binding to α1-syntrophin increases membrane density of human Kir2.1, Kir2.2 and Nav1.5 channels.

Author information

1
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain.
2
Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109, USA Department of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109, USA.
3
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain rcaballero@med.ucm.es.

Abstract

AIMS:

Cardiac excitability and refractoriness are largely determined by the function and number of inward rectifier K⁺ channels (Kir2.1-2.3), which are differentially expressed in the atria and ventricles, and Nav1.5 channels. We have focused on how Nav1.5 and Kir2.x function within a macromolecular complex by elucidating the molecular determinants that govern Nav1.5/Kir2.x reciprocal modulation.

METHODS AND RESULTS:

The results demonstrate that there is an unexpected 'internal' PDZ-like binding domain located at the N-terminus of the Nav1.5 channel that mediates its binding to α1-syntrophin. Nav1.5 N-terminal domain, by itself (the 132 aa peptide) (Nter), exerts a 'chaperone-like' effect that increases sodium (I(Na)) and inward rectifier potassium (I(K1)) currents by enhancing the expression of Nav1.5, Kir2.1, and Kir2.2 channels as demonstrated in Chinese hamster ovary (CHO) cells and in rat cardiomyocytes. Site-directed mutagenesis analysis demonstrates that the Nter chaperone-like effect is determined by Serine 20. Nav1.5-Kir2.x reciprocal positive interactions depend on a specific C-terminal PDZ-binding domain sequence (SEI), which is present in Kir2.1 and Kir2.2 channels but not in Kir2.3. Therefore, in human atrial myocytes, the presence of Kir2.3 isoforms precludes reciprocal I(K1)-INa density modulation. Moreover, results in rat and human atrial myocytes demonstrate that binding to α1-syntrophin is necessary for the Nav1.5-Kir2.x-positive reciprocal modulation.

CONCLUSIONS:

The results demonstrate the critical role of the N-terminal domain of Nav1.5 channels in Nav1.5-Kir2.x-reciprocal interactions and suggest that the molecular mechanisms controlling atrial and ventricular cellular excitability may be different.

KEYWORDS:

Inward rectifier current; Kir2.x; Sodium current; α1-syntrophin

PMID:
26786162
PMCID:
PMC4836625
DOI:
10.1093/cvr/cvw009
[Indexed for MEDLINE]
Free PMC Article

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