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

Abstract

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.

RyR2 regulates Cx43 hemichannel intracellular Ca2+-dependent activation in cardiomyocytes

“…2b-c). Comparable caffeine-triggered fast spiking channel activity has been reported in cardiomyocytes by others [56][57][58] , but the single channel conductances were different (RyR, polycystin-2-like channels) from those reported here, were found in atrial cardiomyocytes (Panx1) or would suffice caffeine stimulation without associated [Ca 2+ ] i elevation (sarcolemmal RyRs). [Ca 2+ ] i activation of Cx43 HCs occurs in a physiological range, up to 500 nM [Ca 2+ ] i , while opening is tempered at higher concentrations and largely decreased at ~800 nM (Fig.…”

Diet and Risk of Atrial Fibrillation - Epidemiologic and Clinical Evidence -

“…Tea and coffee are predominant sources of caffeine,52 and are high in antioxidants55 which may reduce the risk of AF 56. In contrast, caffeine has been shown to have many proarrhythmic effects including changes in the activation of cardiac channels 57, 58. Thus, while the mechanism driving the relationship between caffeine intake and AF is unclear, it may be multifactorial, and could have competing effects.…”

In pursuit of ryanodine receptors gating in the plasma membrane of RINm5F pancreatic β-cells

“…[10][11][12] Partly because of low expression levels, partly because of uncertainty of channel orientation within the membrane and partly because of the difficulty in finding or using RyR-specific regulators, it has proved very difficult to unequivocally verify these ion channels as RyR. Rosker and collegues (2009) encounter similar difficulties.…”