Normal activation–inactivation coupling in sodium channels insures that inactivation is slow at small but rapid at large depolarizations. M1651Q/M1652Q substitutions in the cytoplasmic loop connecting the fourth and fifth transmembrane segments of Domain 4 (S4–S5/D4) of the human heart sodium channel subtype 1 (hH1) affect the kinetics and voltage dependence of inactivation (Tang, L., R.G. Kallen, and R. Horn. 1996. J. Gen. Physiol. 108:89–104.). We now show that glutamine substitutions NH2-terminal to the methionines (L1646, L1647, F1648, A1649, L1650) also influence the kinetics and voltage dependence of inactivation compared with the wild-type channel. In contrast, mutations at the COOH-terminal end of the S4–S5/D4 segment (L1654, P1655, A1656) are without significant effect. Strikingly, the A1649Q mutation renders the current decay time constants virtually voltage independent and decreases the voltage dependences of steady state inactivation and the time constants for the recovery from inactivation. Single-channel measurements show that at negative voltages latency times to first opening are shorter and less voltage dependent in A1649Q than in wild-type channels; peak open probabilities are significantly smaller and the mean open times are shorter. This indicates that the rate constants for inactivation and, probably, activation are increased at negative voltages by the A1649Q mutation reminiscent of Y1494Q/ Y1495Q mutations in the cytoplasmic loop between the third and fourth domains (O'Leary, M.E., L.Q. Chen, R.G. Kallen, and R. Horn. 1995. J. Gen. Physiol. 106:641–658.). Other substitutions, A1649S and A1649V, decrease but fail to eliminate the voltage dependence of time constants for inactivation, suggesting that the decreased hydrophobicity of glutamine at either residues A1649 or Y1494Y1495 may disrupt a linkage between S4–S5/D4 and the interdomain 3–4 loop interfering with normal activation–inactivation coupling.
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1 May 1998
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May 01 1998
Glutamine Substitution at Alanine1649 in the S4–S5 Cytoplasmic Loop of Domain 4 Removes the Voltage Sensitivity of Fast Inactivation in the Human Heart Sodium Channel
Lihui Tang,
Lihui Tang
From the *Department of Biochemistry and Biophysics, and §Mahoney Institute of Neurological Sciences, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6059; and ‡Department of Neurobiology and Anatomy, Allegheny University of Health Sciences, Philadelphia, Pennsylvania 19102-1192
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Nabil Chehab,
Nabil Chehab
From the *Department of Biochemistry and Biophysics, and §Mahoney Institute of Neurological Sciences, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6059; and ‡Department of Neurobiology and Anatomy, Allegheny University of Health Sciences, Philadelphia, Pennsylvania 19102-1192
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Steven J. Wieland,
Steven J. Wieland
From the *Department of Biochemistry and Biophysics, and §Mahoney Institute of Neurological Sciences, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6059; and ‡Department of Neurobiology and Anatomy, Allegheny University of Health Sciences, Philadelphia, Pennsylvania 19102-1192
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Roland G. Kallen
Roland G. Kallen
From the *Department of Biochemistry and Biophysics, and §Mahoney Institute of Neurological Sciences, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6059; and ‡Department of Neurobiology and Anatomy, Allegheny University of Health Sciences, Philadelphia, Pennsylvania 19102-1192
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Lihui Tang
From the *Department of Biochemistry and Biophysics, and §Mahoney Institute of Neurological Sciences, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6059; and ‡Department of Neurobiology and Anatomy, Allegheny University of Health Sciences, Philadelphia, Pennsylvania 19102-1192
Nabil Chehab
From the *Department of Biochemistry and Biophysics, and §Mahoney Institute of Neurological Sciences, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6059; and ‡Department of Neurobiology and Anatomy, Allegheny University of Health Sciences, Philadelphia, Pennsylvania 19102-1192
Steven J. Wieland
From the *Department of Biochemistry and Biophysics, and §Mahoney Institute of Neurological Sciences, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6059; and ‡Department of Neurobiology and Anatomy, Allegheny University of Health Sciences, Philadelphia, Pennsylvania 19102-1192
Roland G. Kallen
From the *Department of Biochemistry and Biophysics, and §Mahoney Institute of Neurological Sciences, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6059; and ‡Department of Neurobiology and Anatomy, Allegheny University of Health Sciences, Philadelphia, Pennsylvania 19102-1192
Address correspondence to Roland G. Kallen, M.D., Ph.D., Department of Biochemistry and Biophysics, 402 Anatomy-Chemistry Building, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6059. Fax: 215-573-7058; E-mail: [email protected]
Received:
July 28 1997
Accepted:
March 16 1998
Online ISSN: 1540-7748
Print ISSN: 0022-1295
1998
J Gen Physiol (1998) 111 (5): 639–652.
Article history
Received:
July 28 1997
Accepted:
March 16 1998
Citation
Lihui Tang, Nabil Chehab, Steven J. Wieland, Roland G. Kallen; Glutamine Substitution at Alanine1649 in the S4–S5 Cytoplasmic Loop of Domain 4 Removes the Voltage Sensitivity of Fast Inactivation in the Human Heart Sodium Channel . J Gen Physiol 1 May 1998; 111 (5): 639–652. doi: https://doi.org/10.1085/jgp.111.5.639
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