Molecular basis for a high-potency open-channel block of Kv1.5 channel by the endocannabinoid anandamide

Molecular Pharmacology
Eloy G Moreno-GalindoRicardo A Navarro-Polanco

Abstract

The endocannabinoid, N-arachidonoylethanolamine (anandamide; AEA) is known to interact with voltage-gated K(+) (Kv) channels in a cannabinoid receptor-independent manner. AEA modulates the functional properties of Kv channels, converting channels with slowly inactivating current into apparent fast inactivation. In this study, we characterize the mechanism of action and binding site for AEA on Kv1.5 channels expressed on HEK-293 cells using the patch-clamp techniques. AEA exhibited high-potency block (IC(50) approximately 200 nM) from the cytoplasmic membrane surface, consistent with open-channel block. Alanine-scanning mutagenesis revealed that AEA interacts with two crucial beta-branching amino acids, Val505 and Ile508 within the S6 domain. Both residues face toward the central cavity and constitute a motif that forms a hydrophobic ring around the ion conduction pathway. This hydrophobic ring motif may be a critical determinant of cannabinoid receptor-independent AEA modulation in other K(+) channel families.

References

Jul 10, 1999·Cell·J M GulbisR MacKinnon
Aug 26, 1999·Life Sciences·B R MartinR K Razdan
Aug 26, 2000·British Journal of Pharmacology·I Van den Bossche, B Vanheel
Sep 27, 2000·Proceedings of the National Academy of Sciences of the United States of America·J S MitchesonM C Sanguinetti
Sep 8, 2001·American Journal of Physiology. Cell Physiology·M C McKay, J F Worley
Oct 28, 2003·The Journal of Biological Chemistry·Niels DecherMichael C Sanguinetti
Aug 16, 2005·Prostaglandins & Other Lipid Mediators·Mario van der Stelt, Vincenzo Di Marzo
Jul 13, 2006·Molecular Pharmacology·Niels DecherMichael C Sanguinetti
Nov 6, 2007·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Nathalie Strutz-SeebohmGuiscard Seebohm
Sep 27, 2008·Journal of Pharmacological Sciences·Iván A AréchigaRicardo A Navarro-Polanco
Nov 7, 2008·The EMBO Journal·Niels DecherMichael C Sanguinetti
Jul 2, 2009·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Sándor Bátkai, Pál Pacher

❮ Previous
Next ❯

Citations

Dec 17, 2010·Cardiovascular Research·Ursula Ravens, Erich Wettwer
May 16, 2012·Biochemical Pharmacology·Yi LiuMan-Wen Jin
May 23, 2012·Biochemical and Biophysical Research Communications·Charles E SpivakMáire E Doyle
Sep 14, 2012·Biochemistry·Natalie SmithersJ Malcolm East
Sep 13, 2011·Journal of Molecular and Cellular Cardiology·Hui-Jun WuGui-Rong Li
Jun 10, 2016·American Journal of Physiology. Cell Physiology·N E FaragM R Boyett
Mar 16, 2017·Frontiers in Pharmacology·Juliet R FooteAnthony W Segal
Sep 29, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Bjørn Olav Hald, Donald G Welsh

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cardiac Conduction System

The cardiac conduction system is a specialized tract of myocardial cells responsible for maintaining normal cardiac rhythm. Discover the latest research on the cardiac conduction system here.