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J Physiol Volume 521, Number 1, 31-42, November 15, 1999
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The Journal of Physiology (1999), 521.1, pp. 31-42
© Copyright 1999 The Physiological Society

Dihydropyridine enantiomers block recombinant L-type Ca2+ channels by two different mechanisms

Renate Handrock, Rose Rao-Schymanski, Norbert Klugbauer *, Franz Hofmann* and Stefan Herzig

Department of Pharmacology, University of Kiel, Hospitalstrasse 4, 24105 Kiel, Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, and * Department of Pharmacology and Toxicology, TU Munich, 80802 Munich, Germany


The molecular basis of the state-dependent block of L-type Ca2+ channels by dihydropyridines is still poorly understood. Therefore, we studied the enantioselectivity of Ca2+ channel block by isradipine enantiomers at three holding potentials (-80, -60 and -40 mV) in Chinese hamster ovary (CHO) cells stably expressing the rabbit lung alpha1C-b-subunit.


The extent of enantioselectivity did not markedly change with the holding potential (IC50 ratios of 104-138), whereas the potency of both isradipine enantiomers increased with depolarisation of the holding potential.


In addition to its block of the peak Ca2+ channel current, Ipeak, (-)-isradipine inhibited the relative current at the end of the test pulse, the so-called Ilate, normalised to Ipeak (Ilate/Ipeak). This effect was unaffected by the holding potential and revealed distinct kinetics compared to the development of conventional block of Ipeak.


When these effects were studied using an alpha1C-b-mutant lacking the high-affinity dihydropyridine binding site, expressed in human embryonic kidney (HEK 293) cells, both enantiomers blocked Ilate/Ipeak to a similar degree.


Our data are discussed within the framework of the 'guarded receptor' and the 'modulated receptor' hypotheses. The very different properties of the block of Ilate/Ipeak compared to those of the conventional high-affinity block of Ipeak suggest the existence of an additional mechanism possibly mediated via a second, distinct binding site.




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