Agonist specific L-type Ca(2+)-current stimulation in ventricular myocytes by a novel steroid-like compound

Keller, Markus; Pignier, Christophe; Santelli, Maurice; Vacher, Bernard; Niggli, Ernst; Egger, Marcel (2006). Agonist specific L-type Ca(2+)-current stimulation in ventricular myocytes by a novel steroid-like compound. Cell calcium, 39(5), pp. 425-33. Amsterdam: Elsevier 10.1016/j.ceca.2006.01.006

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In cardiac muscle the amplitude of Ca(2+) transients can be increased by enhancing Ca(2+) influx. Among the processes leading to increased Ca(2+) influx, agonists of the L-type Ca(2+)-channel can play an important role. Known pharmacological Ca(2+)-channel agonists act on different binding sites on the channel protein, which may lead not only to enhanced peak currents, but also to distinct changes in other biophysical characteristics of the current. In this study, membrane currents were recorded with the patch-clamp technique in the whole-cell configuration in guinea pig isolated ventricular myocytes in combination with confocal fluorescence Ca(2+) imaging techniques and a variety of pharmacological tools. Testing a new positive inotropic steroid-like compound, we found that it increased the L-type Ca(2+)-current by 2.5-fold by shifting the voltage-dependence of activation by 20.2 mV towards negative potentials. The dose-response relationship revealed two vastly different affinities (EC(50(high-affinity))=4.5+/-1.7 nM, EC(50(low-affinity))=8.0+/-1.1 microM) exhibiting differential pharmacological interactions with three classes of Ca(2+)-current antagonists, suggesting more than one binding site on the channel protein. Therefore, we identified and characterized a novel positive inotropic compound (F90927) as a member of a new class of Ca(2+)-channel agonists exhibiting unique features, which set it apart from other presently known L-type Ca(2+)-channel agonists.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Physiology

UniBE Contributor:

Keller, Markus; Niggli, Ernst and Egger, Marcel

ISSN:

0143-4160

ISBN:

16540165

Publisher:

Elsevier

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:45

Last Modified:

06 Dec 2013 13:41

Publisher DOI:

10.1016/j.ceca.2006.01.006

PubMed ID:

16540165

Web of Science ID:

000236998700005

URI:

https://boris.unibe.ch/id/eprint/18502 (FactScience: 665)

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