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Bupivacaine Blocks N-Type Inactivating K-v Channels in the Open State: No Allosteric Effect on Inactivation Kinetics
Karolinska Institute.
University of Munster, Germany.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Karolinska Institute.
2008 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 95, no 11, 5138-5152 p.Article in journal (Refereed) Published
Abstract [en]

Local anesthetics bind to ion channels in a state-dependent manner. For noninactivating voltage-gated K channels the binding mainly occurs in the open state, while for voltage-gated inactivating Na channels it is assumed to occur mainly in inactivated states, leading to an allosterically caused increase in the inactivation probability, reflected in a negative shift of the steady-state inactivation curve, prolonged recovery from inactivation, and a frequency-dependent block. How local anesthetics bind to N-type inactivating K channels is less explored. In this study, we have compared bupivacaine effects on inactivating (Shaker and K(v)3.4) and noninactivating (Shaker-IR and K(v)3.2) channels, expressed in Xenopus oocytes. Bupivacaine was found to block these channels time-dependently without shifting the steady-state inactivation curve markedly, without a prolonged recovery from inactivation, and without a frequency-dependent block. An analysis, including computational testing of kinetic models, suggests binding to the channel mainly in the open state, with affinities close to those estimated for corresponding noninactivating channels (300 and 280 mu M for Shaker and Shaker-IR, and 60 and 90 mu M for K(v)3.4 and K(v)3.2). The similar magnitudes of K-d, as well as of blocking and unblocking rate constants for inactivating and noninactivating Shaker channels, most likely exclude allosteric interactions between the inactivation mechanism and the binding site. The relevance of these results for understanding the action of local anesthetics on Na channels is discussed.

Place, publisher, year, edition, pages
2008. Vol. 95, no 11, 5138-5152 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-16158DOI: 10.1529/biophysj.108.130518OAI: diva2:133247

Original Publication: Johanna Nilsson, Michael Madeja, Fredrik Elinder and Peter Arhem, Bupivacaine Blocks N-Type Inactivating K-v Channels in the Open State: No Allosteric Effect on Inactivation Kinetics, 2008, BIOPHYSICAL JOURNAL, (95), 11, 5138-5152. Copyright: Biophysical Society

Available from: 2009-01-26 Created: 2009-01-07 Last updated: 2013-10-15Bibliographically approved

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