Contribution of BKCa-Channel Activity in Human Cardiac Fibroblasts to Electrical Coupling of Cardiomyocytes-Fibroblasts

Abstract

Cardiac fibroblasts are involved in the maintenance of myocardial tissue structure. However, little is known about ion currents in human cardiac fibroblasts. It has been recently reported that cardiac fibroblasts can interact electrically with cardiomyocytes through gap junctions. Ca(2+)-activated K(+) currents (I (K[Ca])) of cultured human cardiac fibroblasts were characterized in this study. In whole-cell configuration, depolarizing pulses evoked I (K(Ca)) in an outward rectification in these cells, the amplitude of which was suppressed by paxilline (1 microM: ) or iberiotoxin (200 nM: ). A large-conductance, Ca(2+)-activated K(+) (BK(Ca)) channel with single-channel conductance of 162 +/- 8 pS was also observed in human cardiac fibroblasts. Western blot analysis revealed the presence of alpha-subunit of BK(Ca) channels. The dynamic Luo-Rudy model was applied to predict cell behavior during direct electrical coupling of cardiomyocytes and cardiac fibroblasts. In the simulation, electrically coupled cardiac fibroblasts also exhibited action potential; however, they were electrically inert with no gap-junctional coupling. The simulation predicts that changes in gap junction coupling conductance can influence the configuration of cardiac action potential and cardiomyocyte excitability. I (k(Ca)) can be elicited by simulated action potential waveforms of cardiac fibroblasts when they are electrically coupled to cardiomyocytes. This study demonstrates that a BK(Ca) channel is functionally expressed in human cardiac fibroblasts. The activity of these BK(Ca) channels present in human cardiac fibroblasts may contribute to the functional activities of heart cells through transfer of electrical signals between these two cell types.

Atrial Arrhythmias After Lung Transplantation

“…4,5 The mechanism of conduction across anticipated surgical lines of block is unclear, although human cardiac fibroblasts have been demonstrated to have an ability to interact electrically with cardiomyocytes through gap junctions. 27 This study may provide some insights into the role of the PVs in postoperative AF. The postoperative setting is characterized by inflammation, hemodynamic stress, and electrolyte imbalances creating a complex milieu in which 30% to 40% of patients have AF.…”

Cardiac Fibroblasts in Cell Culture Systems: Myofibroblasts All Along?

“…58 Apart from K + inward rectifying currents that determine the resting membrane potential, other K + currents found were transient outward currents, delayedrectifier K + currents and currents carried by Ca 2+ -activated largeconductance K + channels. [58][59][60][61] Importantly, myofibroblasts also express a number of transient receptor-potential channels. 62 Because these cation conducting channels show only weak voltage sensitivity or are constitutively open, they are likely to contribute to the moderate membrane polarization of fibroblasts that is, as described subsequently, instrumental for the establishment of arrhythmogenic interactions between myofibroblasts and cardiomyocytes after establishment of heterocellular electrical coupling.…”

Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression

“…40 In vitro studies show gap junctional coupling through connexin-43 and connexin-45 proteins between cardiomyocytes and myofibroblasts, although big-conductance Ca 2+ -activated K + channels may also play a role. 41,42 Computational analyses suggest that electrotonic myofibroblast-cardiomyocyte interactions can promote diastolic depolarization of atrial cardiomyocytes because of the relatively depolarized membrane potential of cardiac fibroblasts (≈−30 mV), thereby promoting DADs and ectopic firing. 45 The molecular mechanisms underlying the initiation of AF were not studied, although APD prolongation with isoprenaline reduces the incidence of AF episodes.…”