An unexpected requirement for brain-type sodium channels for control of heart rate in the mouse sinoatrial node.

Abstract:

:Voltage-gated Na(+) channels are composed of pore-forming alpha and auxiliary beta subunits. The majority of Na(+) channels in the heart contain tetrodotoxin (TTX)-insensitive Na(v)1.5 alpha subunits, but TTX-sensitive brain-type Na(+) channel alpha subunits are present and functionally important in the transverse tubules of ventricular myocytes. Sinoatrial (SA) nodal cells were identified in cardiac tissue sections by staining for connexin 43 (which is expressed in atrial tissue but not in SA node), and Na(+) channel localization was analyzed by immunocytochemical staining with subtype-specific antibodies and confocal microscopy. Brain-type TTX-sensitive Na(v)1.1 and Na(v)1.3 alpha subunits and all four beta subunits were present in mouse SA node, but Na(v)1.5 alpha subunits were not. Na(v)1.1 alpha subunits were also present in rat SA node. Isolated mouse hearts were retrogradely perfused in a Langendorff preparation, and electrocardiograms were recorded. Spontaneous heart rate and cycle length were constant, and heart rate variability was small under control conditions. In contrast, in the presence of 100 nM TTX to block TTX-sensitive Na(+) channels specifically, we observed a significant reduction in spontaneous heart rate and markedly greater heart rate variability, similar to sick-sinus syndrome in man. We hypothesize that brain-type Na(+) channels are required because their more positive voltage dependence of inactivation allows them to function at the depolarized membrane potential of SA nodal cells. Our results demonstrate an important contribution of TTX-sensitive brain-type Na(+) channels to SA nodal automaticity in mouse heart and suggest that they may also contribute to SA nodal function and dysfunction in human heart.

authors

Maier SK,Westenbroek RE,Yamanushi TT,Dobrzynski H,Boyett MR,Catterall WA,Scheuer T

doi

10.1073/pnas.2627986100

keywords:

subject

Has Abstract

pub_date

2003-03-18 00:00:00

pages

3507-12

issue

6

eissn

0027-8424

issn

1091-6490

pii

2627986100

journal_volume

100

pub_type

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