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Mutations of the S4-S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes.
J Physiol. 1999 Feb 01; 514 (Pt 3):667-75.JP

Abstract

1. The structural basis for the activation gate of voltage-dependent K+ channels is not known, but indirect evidence has implicated the S4-S5 linker, the cytoplasmic region between the fourth and fifth transmembrane domains of the channel subunit. We have studied the effects of mutations in the S4-S5 linker of HERG (human ether-á-go-go-related gene), a human delayed rectifier K+ channel, in Xenopus oocytes. 2. Mutation of acidic residues (D540, E544) in the S4-S5 linker of HERG channels to neutral (Ala) or basic (Lys) residues accelerated the rate of channel deactivation. Most mutations greatly accelerated the rate of activation. However, E544K HERG channels activated more slowly than wild-type HERG channels. 3. Mutation of residues in the S4-S5 linker had little or no effect on fast inactivation, consistent with independence of HERG channel activation and inactivation 4. In response to large hyperpolarizations, D540K HERG channels can reopen into a state that is distinct from the normal depolarization-induced open state. It is proposed that substitution of a negatively charged Asp with the positively charged Lys disrupts a subunit interaction that normally stabilizes the channel in a closed state at negative transmembrane potentials. 5. The results indicate that the S4-S5 linker is a crucial component of the activation gate of HERG channels.

Authors+Show Affiliations

Eccles Program in Human Molecular Biology and Genetics, Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City,UT 84112, USA.mike.sanguinetti@hci.utah.eduNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9882738

Citation

Sanguinetti, M C., and Q P. Xu. "Mutations of the S4-S5 Linker Alter Activation Properties of HERG Potassium Channels Expressed in Xenopus Oocytes." The Journal of Physiology, vol. 514 (Pt 3), 1999, pp. 667-75.
Sanguinetti MC, Xu QP. Mutations of the S4-S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes. J Physiol. 1999;514 (Pt 3):667-75.
Sanguinetti, M. C., & Xu, Q. P. (1999). Mutations of the S4-S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes. The Journal of Physiology, 514 (Pt 3), 667-75.
Sanguinetti MC, Xu QP. Mutations of the S4-S5 Linker Alter Activation Properties of HERG Potassium Channels Expressed in Xenopus Oocytes. J Physiol. 1999 Feb 1;514 (Pt 3):667-75. PubMed PMID: 9882738.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations of the S4-S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes. AU - Sanguinetti,M C, AU - Xu,Q P, PY - 1999/1/12/pubmed PY - 1999/1/12/medline PY - 1999/1/12/entrez SP - 667 EP - 75 JF - The Journal of physiology JO - J Physiol VL - 514 (Pt 3) N2 - 1. The structural basis for the activation gate of voltage-dependent K+ channels is not known, but indirect evidence has implicated the S4-S5 linker, the cytoplasmic region between the fourth and fifth transmembrane domains of the channel subunit. We have studied the effects of mutations in the S4-S5 linker of HERG (human ether-á-go-go-related gene), a human delayed rectifier K+ channel, in Xenopus oocytes. 2. Mutation of acidic residues (D540, E544) in the S4-S5 linker of HERG channels to neutral (Ala) or basic (Lys) residues accelerated the rate of channel deactivation. Most mutations greatly accelerated the rate of activation. However, E544K HERG channels activated more slowly than wild-type HERG channels. 3. Mutation of residues in the S4-S5 linker had little or no effect on fast inactivation, consistent with independence of HERG channel activation and inactivation 4. In response to large hyperpolarizations, D540K HERG channels can reopen into a state that is distinct from the normal depolarization-induced open state. It is proposed that substitution of a negatively charged Asp with the positively charged Lys disrupts a subunit interaction that normally stabilizes the channel in a closed state at negative transmembrane potentials. 5. The results indicate that the S4-S5 linker is a crucial component of the activation gate of HERG channels. SN - 0022-3751 UR - https://www.unboundmedicine.com/medline/citation/9882738/Mutations_of_the_S4_S5_linker_alter_activation_properties_of_HERG_potassium_channels_expressed_in_Xenopus_oocytes_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3751&date=1999&volume=514&spage=667 DB - PRIME DP - Unbound Medicine ER -