Molecular mechanism of diltiazem interaction with L-type Ca2+ channels.

The Journal of Biological Chemistry
R L KrausJ Striessnig

Abstract

Benzothiazepine Ca2+ antagonists (such as (+)-cis-diltiazem) interact with transmembrane segments IIIS6 and IVS6 in the alpha1 subunit of L-type Ca2+ channels. We investigated the contribution of individual IIIS6 amino acid residues for diltiazem sensitivity by employing alanine scanning mutagenesis in a benzothiazepine-sensitive alpha1 subunit chimera (ALDIL) expressed in Xenopus laevis oocytes. The most dramatic decrease of block by 100 microM diltiazem (ALDIL 45 +/- 4.8% inhibition) during trains of 100-ms pulses (0.1 Hz, -80 mV holding potential) was found after mutation of adjacent IIIS6 residues Phe1164(21 +/- 3%) and Val1165 (8.5 +/- 1.4%). Diltiazem delayed current recovery by promoting a slowly recovering current component. This effect was similar in ALDIL and F1164A but largely prevented in V1165A. Both mutations slowed inactivation kinetics during a pulse. The reduced diltiazem block can therefore be explained by slowing of inactivation kinetics (F1164A and V1165A) and accelerated recovery from drug block (V1165A). The bulkier diltiazem derivative benziazem still efficiently blocked V1165A. From these functional and from additional radioligand binding studies with the dihydropyridine (+)-[3H]isradipine we propose a m...Continue Reading

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Citations

Apr 8, 2003·European Journal of Pharmacology·Masafumi HagiwaraTaku Nagao
Apr 17, 2003·Experimental Eye Research·Jason HartSteven Barnes
May 24, 2000·British Journal of Pharmacology·P EllerJ Striessnig
Feb 28, 2003·Biology of Reproduction·David P LuChristopher O'Neill
Nov 17, 2001·The Journal of Physiology·R MarksteinerS Hering
Oct 27, 2010·British Journal of Pharmacology·W ShabbirS Hering
Jul 25, 2015·Biochemical Pharmacology·Terrance P Snutch, Gerald W Zamponi
Mar 19, 2019·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Matteo OttoliniSwapnil K Sonkusare
Mar 22, 2003·Journal of Neurophysiology·Jozsef VighEric M Lasater
Apr 10, 2008·The Journal of Biological Chemistry·Denis B Tikhonov, Boris S Zhorov
May 4, 2007·The Journal of Pharmacology and Experimental Therapeutics·Alexandra ZahradníkováIvan Zahradník
Nov 28, 2000·Molecular Pharmacology·G H HockermanW A Catterall
Aug 9, 2019·Molecular Pharmacology·Lin TangWilliam A Catterall
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