Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 329, Issue 2, Pages 780-788Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2005.02.039
Keywords
sodium channel; acetyl-KIFMK-amide; fast inactivation; IFM motif; local anesthetics; tail currents; inactivation-deficient Na+
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Funding
- NHLBI NIH HHS [HL 66076] Funding Source: Medline
- NIGMS NIH HHS [GM 48090] Funding Source: Medline
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The Na+ channel alpha-subunit contains an IFM motif that is critical for the fast inactivation process. In this study, we sought to determine whether an IFM-containing peptide, acetyl-KIFMK-amide, blocks open cardiac Na+ channels via the inner cavity. Intracellular acetyl-KIFMK-amide at 2 mM elicited a rapid time-dependent block (tau = 0.24 ms) of inactivation-deficient human heart Na+ channels (hNav1.5-L409C/A410W) at +50 rnV. In addition, a peptide-induced tail current appeared conspicuously upon repolarization, suggesting that the activation gate cannot close until acetyl-KIFMK-amide is cleared from the open pore. Repetitive pulses (+50 mV for 20 ins at 1 Hz) produced a substantial use-dependent block of both peak and tail currents by similar to 65%. A F1760K mutation (hNav1.5-L409C/A410W/F1760K) abolished the use-dependent block by acetyl-KIFMK-amide and hindered the time-dependent block. Competition experiments showed that acetyl-KIFMK-amide antagonized bupivacaine binding. These results are consistent with a model that two acetyl-KIFMK-amide receptors exist in proximity within the Na+ channel inner cavity. (c) 2005 Elsevier Inc. All rights reserved.
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