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Inactivation gating determines nicotine blockade of human HERG channels.
Am J Physiol. 1999 09; 277(3):H1081-8.AJ

Abstract

We have previously found that nicotine blocked multiple K+ currents, including the rapid component of delayed rectifier K+ currents (IKr), by interacting directly with the channels. To shed some light on the mechanisms of interaction between nicotine and channels, we performed detailed analysis on the human ether-à-go-go-related gene (HERG) channels, which are believed to be equivalent to the native I(Kr) when expressed in Xenopus oocytes. Nicotine suppressed the HERG channels in a concentration-dependent manner with greater potency with voltage protocols, which favor channel inactivation. Nicotine caused dramatic shifts of the voltage-dependent inactivation curve to more negative potentials and accelerated the inactivation process. Conversely, maneuvers that weakened the channel inactivation gating considerably relieved the blockade. Elevating the extracellular K+ concentration from 5 to 20 mM increased the nicotine concentration (by approximately 100-fold) needed to achieve the same degree of inhibition. Moreover, nicotine lost its ability to block the HERG channels when a single mutation was introduced to a residue located after transmembrane domain 6 (S631A) to remove the rapid channel inactivation. Our data suggest that the inactivation gating determines nicotine blockade of the HERG channels.

Authors+Show Affiliations

Research Center, Montreal Heart Institute, Montreal H1T 1C8, Quebec, Canada H3C 3J7.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

10484431

Citation

Wang, H Z., et al. "Inactivation Gating Determines Nicotine Blockade of Human HERG Channels." The American Journal of Physiology, vol. 277, no. 3, 1999, pp. H1081-8.
Wang HZ, Shi H, Liao SJ, et al. Inactivation gating determines nicotine blockade of human HERG channels. Am J Physiol. 1999;277(3):H1081-8.
Wang, H. Z., Shi, H., Liao, S. J., & Wang, Z. (1999). Inactivation gating determines nicotine blockade of human HERG channels. The American Journal of Physiology, 277(3), H1081-8. https://doi.org/10.1152/ajpheart.1999.277.3.H1081
Wang HZ, et al. Inactivation Gating Determines Nicotine Blockade of Human HERG Channels. Am J Physiol. 1999;277(3):H1081-8. PubMed PMID: 10484431.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inactivation gating determines nicotine blockade of human HERG channels. AU - Wang,H Z, AU - Shi,H, AU - Liao,S J, AU - Wang,Z, PY - 1999/9/14/pubmed PY - 1999/9/14/medline PY - 1999/9/14/entrez SP - H1081 EP - 8 JF - The American journal of physiology JO - Am J Physiol VL - 277 IS - 3 N2 - We have previously found that nicotine blocked multiple K+ currents, including the rapid component of delayed rectifier K+ currents (IKr), by interacting directly with the channels. To shed some light on the mechanisms of interaction between nicotine and channels, we performed detailed analysis on the human ether-à-go-go-related gene (HERG) channels, which are believed to be equivalent to the native I(Kr) when expressed in Xenopus oocytes. Nicotine suppressed the HERG channels in a concentration-dependent manner with greater potency with voltage protocols, which favor channel inactivation. Nicotine caused dramatic shifts of the voltage-dependent inactivation curve to more negative potentials and accelerated the inactivation process. Conversely, maneuvers that weakened the channel inactivation gating considerably relieved the blockade. Elevating the extracellular K+ concentration from 5 to 20 mM increased the nicotine concentration (by approximately 100-fold) needed to achieve the same degree of inhibition. Moreover, nicotine lost its ability to block the HERG channels when a single mutation was introduced to a residue located after transmembrane domain 6 (S631A) to remove the rapid channel inactivation. Our data suggest that the inactivation gating determines nicotine blockade of the HERG channels. SN - 0002-9513 UR - https://www.unboundmedicine.com/medline/citation/10484431/Inactivation_gating_determines_nicotine_blockade_of_human_HERG_channels_ L2 - https://journals.physiology.org/doi/10.1152/ajpheart.1999.277.3.H1081?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -