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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/H2448    most recent 00032.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y.-a. Articles by Zou, H. Search for Related Content PubMed PubMed Citation Articles by Zhang, Y.-a. Articles by Zou, H.

Caffeine-activated large-conductance plasma membrane cation channels in cardiac myocytes: characteristics and significance

¹Department of Physiology and ²Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, Massachusetts

Submitted 9 January 2007 ; accepted in final form 1 May 2007

Caffeine-activated, large-conductance, nonselective cation channels (LCCs) have been found in the plasma membrane of isolated cardiac myocytes in several species. However, little is known about the effects of opening these channels. To examine such effects and to further understand the caffeine-activation mechanism, we carried out studies using whole-cell patch-clamp techniques with freshly isolated cardiac myocytes from rats and mice. Unlike previous studies, thapsigargin was used so that both the effect of opening LCCs and the action of caffeine were independent of Ca²⁺ release from intracellular stores. These Ca²⁺-permeable LCCs were found in a majority of the cells from atria and ventricles, with a conductance of 370 pS in rat atria. Caffeine and all its direct metabolic products (theophylline, theobromine, and paraxanthine) activated the channel, while isocaffeine did not. Although they share some similarities with ryanodine receptors (RyRs, the openings of which give rise to Ca²⁺ sparks), LCCs also showed some different characteristics. With simultaneous Ca²⁺ imaging and current recording, the localized fluorescence increase due to Ca²⁺ entry through a single opening of an LCC (SCCaFT) was detected. When membrane potential, instead of current, was recorded, SCCaFT-like fluorescence transients (indicating single LCC openings) were found to accompany membrane depolarizations. To our knowledge, this is the first report directly linking membrane potential changes to a single opening of an ion channel. Moreover, these events in cardiac cells suggest a possible additional mechanism by which caffeine and theophylline contribute to the generation of cardiac arrhythmias.

ryanodine receptor; methylxanthine; single-channel calcium fluorescence transients; calcium sparks; cardiac arrhythmia