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

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. Ca2+-activated K+ currents (IK[Ca]) of cultured human cardiac fibroblasts were characterized in this study. In whole-cell configuration, depolarizing pulses evoked IK(Ca) in an outward rectification in these cells, the amplitude of which was suppressed by paxilline (1 μM) or iberiotoxin (200 nM). A large-conductance, Ca2+-activated K+ (BKCa) channel with single-channel conductance of 162 ± 8 pS was also observed in human cardiac fibroblasts. Western blot analysis revealed the presence of α-subunit of BKCa 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. Ik(Ca) can be elicited by simulated action potential waveforms of cardiac fibroblasts when they are electrically coupled to cardiomyocytes. This study demonstrates that a BKCa channel is functionally expressed in human cardiac fibroblasts. The activity of these BKCa 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.

[1]  R Latorre,et al.  Gating kinetics of Ca2+-activated K+ channels from rat muscle incorporated into planar lipid bilayers. Evidence for two voltage- dependent Ca2+ binding reactions , 1983, The Journal of general physiology.

[2]  L. Salkoff,et al.  mSlo, a complex mouse gene encoding "maxi" calcium-activated potassium channels. , 1993, Science.

[3]  C. Luo,et al.  A dynamic model of the cardiac ventricular action potential. II. Afterdepolarizations, triggered activity, and potentiation. , 1994, Circulation research.

[4]  C. Luo,et al.  A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. , 1994, Circulation research.

[5]  Min-Cheol Song,et al.  Molecular constituents of maxi KCa channels in human coronary smooth muscle: predominant α+β subunit complexes , 1997 .

[6]  T. Hwang,et al.  Activation of muscarinic K+ channels by extracellular ATP and UTP in rat atrial myocytes. , 1998, Journal of cardiovascular pharmacology.

[7]  Neil V Marrion,et al.  Calcium-activated potassium channels , 1998, Current Opinion in Neurobiology.

[8]  Y. Kudo,et al.  Properties and expression of Ca2+-activated K+ channels in H9c2 cells derived from rat ventricle. , 1999, American journal of physiology. Heart and circulatory physiology.

[9]  Properties and expression of Ca2+-activated K+ channels in H9c2 cells derived from rat ventricle. , 1999, American journal of physiology. Heart and circulatory physiology.

[10]  R. Aldrich,et al.  Allosteric Voltage Gating of Potassium Channels I , 1999, The Journal of general physiology.

[11]  R. Aldrich,et al.  Allosteric Voltage Gating of Potassium Channels I: Mslo Ionic Currents in the Absence of Ca2+ , 1999 .

[12]  P. Hunter,et al.  Stretch-induced changes in heart rate and rhythm: clinical observations, experiments and mathematical models. , 1999, Progress in biophysics and molecular biology.

[13]  K. Magleby,et al.  Gating Kinetics of Single Large-Conductance Ca2+-Activated K+ Channels in High Ca2+ Suggest a Two-Tiered Allosteric Gating Mechanism✪ , 1999, The Journal of general physiology.

[14]  L. Birnbaumer,et al.  Cloning of Trp1β isoform from rat brain: immunodetection and localization of the endogenous Trp1 protein. , 1999, American journal of physiology. Cell physiology.

[15]  N. Standen,et al.  A residue in the intracellular vestibule of the pore is critical for gating and permeation in Ca2+‐activated K+ (BKCa) channels , 2000, The Journal of physiology.

[16]  C. Peracchia,et al.  Chemical gating of gap junction channels. , 2000, Methods.

[17]  Y Rudy,et al.  Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death. , 2001, Cardiovascular research.

[18]  Sheng-Nan Wu,et al.  Characterization of action potential waveform-evoked L-type calcium currents in pituitary GH3 cells , 2001, Pflügers Archiv.

[19]  B. Greenberg,et al.  Molecular Medicine Tumor Necrosis Factor-�–Induced AT 1 Receptor Upregulation Enhances Angiotensin II–Mediated Cardiac Fibroblast Responses That Favor Fibrosis , 2022 .

[20]  Fast and Slow Time Scales , 2002 .

[21]  Bard Ermentrout,et al.  Simulating, analyzing, and animating dynamical systems - a guide to XPPAUT for researchers and students , 2002, Software, environments, tools.

[22]  Sheng-Nan Wu.  Large-conductance Ca2+- activated K+ channels:physiological role and pharmacology. , 2003, Current medicinal chemistry.

[23]  Sheng-Nan Wu,et al.  Behavior of Nonselective Cation Channels and Large‐Conductance Ca2+‐Activated K+ Channels Induced by Dynamic Changes in Membrane Stretch in Cultured Smooth Muscle Cells of Human Coronary Artery , 2003, Journal of cardiovascular electrophysiology.

[24]  A. Bonev,et al.  Modulation of the molecular composition of large conductance, Ca(2+) activated K(+) channels in vascular smooth muscle during hypertension. , 2003, The Journal of clinical investigation.

[25]  Sheng-Nan Wu,et al.  Stimulatory effects of squamocin, an Annonaceous acetogenin, on Ca(2+)-activated K+ current in cultured smooth muscle cells of human coronary artery. , 2003, Chemical research in toxicology.

[26]  Yi Zhang,et al.  Molecular Identification and Functional Roles of a Ca2+-activated K+ Channel in Human and Mouse Hearts* , 2003, Journal of Biological Chemistry.

[27]  M. Miragoli,et al.  Coupling of Cardiac Electrical Activity Over Extended Distances by Fibroblasts of Cardiac Origin , 2003, Circulation research.

[28]  D. Noble,et al.  A model for human ventricular tissue. , 2004, American journal of physiology. Heart and circulatory physiology.

[29]  I. LeGrice,et al.  Fibroblast Network in Rabbit Sinoatrial Node: Structural and Functional Identification of Homogeneous and Heterogeneous Cell Coupling , 2004, Circulation research.

[30]  Ming-Wei Lin,et al.  Stimulatory Actions of Caffeic Acid Phenethyl Ester, a Known Inhibitor of NF-κB Activation, on Ca2+-activated K+ Current in Pituitary GH3 Cells* , 2004, Journal of Biological Chemistry.

[31]  P. Bois,et al.  Functional characterization of a Ca2+‐activated non‐selective cation channel in human atrial cardiomyocytes , 2004, The Journal of physiology.

[32]  W. Giles,et al.  A voltage‐dependent K+ current contributes to membrane potential of acutely isolated canine articular chondrocytes , 2004, The Journal of physiology.

[33]  Stephan Rohr,et al.  Role of gap junctions in the propagation of the cardiac action potential. , 2004, Cardiovascular research.

[34]  Camillo Peracchia,et al.  Chemical gating of gap junction channels; roles of calcium, pH and calmodulin. , 2004, Biochimica et biophysica acta.

[35]  Peter Kohl,et al.  Electrical coupling of fibroblasts and myocytes: relevance for cardiac propagation. , 2005, Journal of electrocardiology.

[36]  H. Nakaya,et al.  Mitochondrial Ca2+-Activated K+ Channels in Cardiac Myocytes: A Mechanism of the Cardioprotective Effect and Modulation by Protein Kinase A , 2005, Circulation.

[37]  W. Giles,et al.  K+ currents regulate the resting membrane potential, proliferation, and contractile responses in ventricular fibroblasts and myofibroblasts. , 2005, American journal of physiology. Heart and circulatory physiology.

[38]  T. Borg,et al.  Structural and functional characterisation of cardiac fibroblasts. , 2005, Cardiovascular research.

[39]  A. Kamkin,et al.  Electrical interaction of mechanosensitive fibroblasts and myocytes in the heart , 2005, Basic Research in Cardiology.

[40]  Yoram Rudy,et al.  Subunit Interaction Determines IKs Participation in Cardiac Repolarization and Repolarization Reserve , 2005, Circulation.

[41]  Ian E. Alexander,et al.  Fibroblasts Can Be Genetically Modified to Produce Excitable Cells Capable of Electrical Coupling , 2005, Circulation.

[42]  Sheng-Nan Wu,et al.  Characterization of chromanol 293B-induced block of the delayed-rectifier K+ current in heart-derived H9c2 cells. , 2005, Life sciences.

[43]  A. Boldt,et al.  The FASEB Journal express article 10.1096/fj.05-4871fje. Published online December 13, 2005. , 2022 .

[44]  Diosgenin, a plant-derived sapogenin, stimulates Ca2+-activated K+ current in human cortical HCN-1A neuronal cells. , 2006, Planta medica.

[45]  V. Jebara,et al.  A voltage-activated proton current in human cardiac fibroblasts. , 2006, Biochemical and biophysical research communications.

[46]  R. Latorre,et al.  Gating Kinetics of Ca "-activated K + Channels from Rat Muscle Incorporated into Planar Lipid Bilayers Evidence for Two Voltage-dependent Ca 2 ' Binding Reactions , 2022 .