Resurgent tail Na+ currents were first discovered in cerebellar Purkinje neurons. A recent study showed that a 14-mer fragment of a mouse β4 subunit, β4154–167, acts as an intracellular open-channel blocker and elicits resurgent currents in Purkinje neurons (Grieco, T.M., J.D. Malhotra, C. Chen, L.L. Isom, and I.M. Raman. 2005. Neuron. 45:233–244). To explore these phenotypes in vitro, we characterized β4154–167 actions in inactivation-deficient cardiac hNav1.5 Na+ channels expressed in human embryonic kidney 293t cells. Intracellular β4154–167 from 25–250 μM elicited a conspicuous time-dependent block of inactivation-deficient Na+ currents at 50 mV in a concentration-dependent manner. On and off rates for β4154–167 binding were estimated at 10.1 μM−1s−1 and 49.1 s−1, respectively. Upon repolarization, large tail currents emerged with a slight delay at −140 mV, probably as a result of the rapid unblocking of β4154–167. Near the activation threshold (approximately −70 mV), resurgent tail currents were robust and long lasting. Likewise, β4154–167 induces resurgent currents in wild-type hNav1.5 Na+ channels, although to a lesser extent. The inactivation peptide acetyl-KIFMK-amide not only restored the fast inactivation phenotype in hNav1.5 inactivation-deficient Na+ channels but also elicited robust resurgent currents. When modified by batrachotoxin (BTX), wild-type hNav1.5 Na+ channels opened persistently but became resistant to β4154–167 and acetyl-KIFMK-amide block. Finally, a lysine substitution of a phenylalanine residue at D4S6, F1760, which forms a part of receptors for local anesthetics and BTX, rendered cardiac Na+ channels resistant to β4154–167. Together, our in vitro studies identify a putative S6-binding site for β4154–167 within the inner cavity of hNav1.5 Na+ channels. Such an S6 receptor readily explains (1) why β4154–167 gains access to its receptor as an open-channel blocker, (2), why bound β4154–167 briefly prevents the activation gate from closing by a “foot-in-the-door” mechanism during deactivation, (3) why BTX inhibits β4154–167 binding by physical exclusion, and (4) why a lysine substitution of residue F1760 eliminates β4154–167 binding.
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1 March 2006
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February 27 2006
Time-Dependent Block and Resurgent Tail Currents Induced by Mouse β4154–167 Peptide in Cardiac Na+ Channels
Ging Kuo Wang,
Ging Kuo Wang
1Department of Anesthesia, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115
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Thomas Edrich,
Thomas Edrich
1Department of Anesthesia, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115
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Sho-Ya Wang
Sho-Ya Wang
2Department of Biology, State University of New York at Albany, Albany, NY 12222
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Ging Kuo Wang
1Department of Anesthesia, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115
Thomas Edrich
1Department of Anesthesia, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115
Sho-Ya Wang
2Department of Biology, State University of New York at Albany, Albany, NY 12222
Correspondence to Ging Kuo Wang: [email protected]
Abbreviations used in this paper: BTX, batrachotoxin; HEK, human embryonic kidney.
Received:
September 09 2005
Accepted:
January 31 2006
Online ISSN: 1540-7748
Print ISSN: 0022-1295
The Rockefeller University Press
2006
J Gen Physiol (2006) 127 (3): 277–289.
Article history
Received:
September 09 2005
Accepted:
January 31 2006
Citation
Ging Kuo Wang, Thomas Edrich, Sho-Ya Wang; Time-Dependent Block and Resurgent Tail Currents Induced by Mouse β4154–167 Peptide in Cardiac Na+ Channels . J Gen Physiol 1 March 2006; 127 (3): 277–289. doi: https://doi.org/10.1085/jgp.200509399
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