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Requirement of neuronal‐ and cardiac‐type sodium channels for murine sinoatrial node pacemaking
Author(s) -
Lei Ming,
Jones Sandra A.,
Liu Jie,
Lancaster Matthew K.,
Fung Simon S.M.,
Dobrzynski Halina,
Camelliti Patrizia,
Maier Sebastian K. G.,
Noble Denis,
Boyett Mark R.
Publication year - 2004
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2004.068643
Subject(s) - tetrodotoxin , sinoatrial node , sodium channel , gene isoform , chemistry , patch clamp , immunocytochemistry , nav1.5 , myocyte , pacemaker potential , electrophysiology , biophysics , microbiology and biotechnology , neuroscience , biology , endocrinology , sodium , biochemistry , heart rate , gene , organic chemistry , blood pressure
The majority of Na + channels in the heart are composed of the tetrodotoxin (TTX)‐resistant ( K D , 2–6 μ m ) Na v 1.5 isoform; however, recently it has been shown that TTX‐sensitive ( K D , 1–10 n m ) neuronal Na + channel isoforms (Na v 1.1, Na v 1.3 and Na v 1.6) are also present and functionally important in the myocytes of the ventricles and the sinoatrial (SA) node. In the present study, in mouse SA node pacemaker cells, we investigated Na + currents under physiological conditions and the expression of cardiac and neuronal Na + channel isoforms. We identified two distinct Na + current components, TTX resistant and TTX sensitive. At 37°C, TTX‐resistant i Na and TTX‐sensitive i Na started to activate at ∼−70 and ∼−60 mV, and peaked at −30 and −10 mV, with a current density of 22 ± 3 and 18 ± 1 pA pF −1 , respectively. TTX‐sensitive i Na inactivated at more positive potentials as compared to TTX‐resistant i Na . Using action potential clamp, TTX‐sensitive i Na was observed to activate late during the pacemaker potential. Using immunocytochemistry and confocal microscopy, different distributions of the TTX‐resistant cardiac isoform, Na v 1.5, and the TTX‐sensitive neuronal isoform, Na v 1.1, were observed: Na v 1.5 was absent from the centre of the SA node, but present in the periphery of the SA node, whereas Na v 1.1 was present throughout the SA node. Nanomolar concentrations (10 or 100 n m ) of TTX, which block TTX‐sensitive i Na , slowed pacemaking in both intact SA node preparations and isolated SA node cells without a significant effect on SA node conduction. In contrast, micromolar concentrations (1–30 μ m ) of TTX, which block TTX‐resistant i Na as well as TTX‐sensitive i Na , slowed both pacemaking and SA node conduction. It is concluded that two Na + channel isoforms are important for the functioning of the SA node: neuronal (putative Na v 1.1) and cardiac Na v 1.5 isoforms are involved in pacemaking, although the cardiac Na v 1.5 isoform alone is involved in the propagation of the action potential from the SA node to the surrounding atrial muscle.