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Proton Modulation of Cardiac Voltage-Gated Sodium Channel Kinetics
D.K. Jones, C.R. Allard, C.H. Peters, T.W. Claydon, & P.C. Ruben
The kinetics of cardiac sodium current are altered during cardiac acidosis. Cardiac
voltage-gated sodium (NaV1.5) channels are blocked by protons via interactions
with outer pore carboxylates. To date, there is no comprehensive description of
proton modulation of NaV1.5 channel voltage-dependence or kinetics, nor have the
amino acid residues potentially responsible been identified. Using the cut-open
voltage clamp technique, we recorded currents from Xenopus oocytes expressing
NaV1.5 with extracellular solution titrated between pH 5 through pH 8. Reducing
extracellular pH from control (pH 7.4) destabilized both the fast-inactivated and
slow-inactivated states in NaV1.5. In addition, acidic pH increased the late sodium
current. Data from mutant NaV1.5 channels suggest histidines of the DII p-loop play
a role in proton sensing, the stability of the slow-inactivated state, and cross talk
between the channel’s voltage sensor and pore. Ventricular action potential models
incorporating WT NaV1.5 currents recorded at extracellular pH 6.0 displayed
arrhythmogenic properties. The action potential maximum rise rate was reduced
and there was an increased heterogeneity of repolarization between epicardial, midmyocardial, and endocardial action potentials.