RT Journal Article
SR Electronic
T1 Molecular Basis for a High-Potency Open Channel Block of Kv1.5 Channel by the Endocannabinoid Anandamide.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.109.063008
DO 10.1124/mol.109.063008
A1 Eloy G Moreno-Galindo
A1 Gabriel F Barrio-Echavarria
A1 Jose C Vasquez
A1 Niels Decher
A1 Frank B Sachse
A1 Martin Tristani-Firouzi
A1 Jose A Sanchez-Chapula
A1 Ricardo A Navarro-Polanco
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/02/04/mol.109.063008.abstract
AB The endocannabinoid, N-arachidonoylethanolamine (anandamide, AEA), is known to interact with voltage-gated K+ (Kv) channels in a 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 (IC50 ≈ 200 nM) from the cytoplasmic membrane surface, consistent with open channel block. Ala-scanning mutagenesis revealed that AEA interacts with two crucial β-branching amino acids, V505 and I508 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 receptor-independent AEA modulation in other K+ channel families.The American Society for Pharmacology and Experimental Therapeutics