Abstract
A large conductance (∼300 picosiemens) channel (LCC) of unknown molecular identity, activated by Ca(2+) release from the sarcoplasmic reticulum, particularly when augmented by caffeine, has been described previously in isolated cardiac myocytes. A potential candidate for this channel is pannexin 1 (Panx1), which has been shown to form large ion channels when expressed in Xenopus oocytes and mammalian cells. Panx1 function is implicated in ATP-mediated auto-/paracrine signaling, and a crucial role in several cell death pathways has been suggested. Here, we demonstrate that after culturing for 4 days LCC activity is no longer detected in myocytes but can be rescued by adenoviral gene transfer of Panx1. Endogenous LCCs and those related to expression of Panx1 share key pharmacological properties previously used for identifying and characterizing Panx1 channels. These data demonstrate that Panx1 constitutes the LCC of cardiac myocytes. Sporadic openings of single Panx1 channels in the absence of Ca(2+) release can trigger action potentials, suggesting that Panx1 channels potentially promote arrhythmogenic activities.
Highlights
large conductance channel (LCC) activities investigated in the quoted studies share some common features beyond their large conductance as follows: they are nonselective cation channels, they can be activated by Ca2ϩ release from the sarcoplasmic reticulum, when synchronized by caffeine; and they appear to have a low density in the plasma membrane or a low open probability
Because sporadic openings of single pannexin 1 (Panx1) channels in the absence of caffeine can trigger action potentials, we suggest that Panx1 channels potentially promote arrhythmogenic activities
Ca2ϩ Release and LCC Activity—In isolated rat myocytes, experimental conditions using citrate as a low affinity Ca2ϩ buffer favor spontaneous cyclic Ca2ϩ release, which activates an inward current carried by electrogenic Naϩ/Ca2ϩ exchange (NCX) [29]
Summary
Connexin; LCC, large conductance channel; Panx, pannexin; NCX, Naϩ/Ca2ϩ-exchange; CBX, carbenoxolone. Several studies have shown that cardiac myocytes from different species express a large conductance channel (LCC) with unknown physiological function [22,23,24,25] This channel responds to spontaneous or caffeine-induced Ca2ϩ release from internal stores and has the paradoxical feature that unitary current fluctuations can be resolved in the whole cell mode of the patch clamp technique, suggesting a very low density of functional channels. We demonstrate that the LCC, activated by Ca2ϩ release from the sarcoplasmic reticulum in cardiac myocytes, shares key pharmacological properties previously used for identifying and characterizing Panx channels. These data are in support of the notion that Panx constitutes this LCC. Because sporadic openings of single Panx channels in the absence of caffeine can trigger action potentials, we suggest that Panx channels potentially promote arrhythmogenic activities
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