Ca ²⁺ Entry Through TRP-C Channels Regulates Fibroblast Biology in Chronic Atrial Fibrillation

Abstract

I n this issue of Circulation, Harada et al 1 provide fundamental new insights into the cellular mechanism(s) for initiation and maintenance of chronic atrial fibrillation in the human heart. The authors, taking what most might still consider to be an unconventional approach to understanding this proarrhythmic substrate, 2,3,4 have identified the atrial fibroblast as an important player. More specifically, this international group of investigators concludes that a particular member of the transient receptor potential or TRP family 5 of ion channels, TRPC3, when expressed/upregulated in human atrial fibroblasts, can contribute to chronic atrial fibrillation. Activation or enhanced expression of TRPC3 provides a means for increased transmembrane calcium entry into the fibroblast. This trigger calcium can then result in a marked increase in proliferation, followed by transformation to the myofibroblast phenotype. 6,7 A previous study had drawn attention to the possibility that a different TRP channel subtype, TRPM7, could play a somewhat similar proarrhythmic role in the atrium. 7,8 Article see p 2051Atrial fibrillation is the most common form of cardiac arrhythmia in adult humans. 9 Importantly, its incidence is projected to increase substantially as a consequence of the association of atrial fibrillation with healthy aging, 10 diabetes mellitus, and hypothyroidism.Harada et al 1 provide the first evidence for the presence of TRPC3 current during the proliferative phase in cultured human atrial fibroblasts. Knockdown of TRPC3 is able to suppress atrial fibroblast proliferation, and similar results were obtained with the pharmacological inhibitor PYR3, a relatively new pyrazole-based compound. This particular TRP channel exhibits significant calcium permeability. This calcium influx contributes to ERK phosphorylation, which is involved in mediating atrial fibroblast proliferation. A very interesting observation is that TRPC expression is markedly reduced and can even disappear when the proliferating fibroblasts eventually adopt a myofibroblast phenotype.Previously, we have shown that members of the TRPC family are importantly involved in the electrophysiological mechanisms that underlie some of the effects of natriuretic peptides (acting through the natriuretic peptide C receptor) in rat ventricle. 8 In this case (although calcium entry and subsequent intracellular calcium waves and altered gene transcription are likely consequences), the electrogenic current through TRP channels is sufficient that connexinmediated electrotonic cell-cell communication from the fibroblast or myofibroblast to the myocyte is altered. This intercellular current flow can change the resting potential, the action potential waveform, or both.We have explored some of these TRP channel-mediated effects using mathematical models of the human atrial myocyte in the presence or absence of electrotonic interaction with a selected number of fibroblasts. It is based on the results of a computation done using 1 human myocyte coupled with 1 fibrobla...

Calcium Channels in the Heart

“…The pathophysiological role of TRP channels in cardiac arrhythmias is an emerging area of interest, and the aforementioned studies strongly indicate the need to better understand the relationships between these ion channels and conduction disturbances in the heart. 136 In conclusion, several ion channels in the heart are responsible for mediating Ca 2+ influx into myocytes and fibroblasts. Ca V 1.2-mediated I Ca,L represents a major route for Ca 2+ entry in all cardiomyocytes throughout the heart, while Ca V 1.3-mediated I Ca,L is restricted to the SAN, the cardiac conduction system, and the atrial myocardium.…”

Tetrandrine reverses human cardiac myofibroblast activation and myocardial fibrosis

“…Voltage-gated Ca 2ϩ channels, known to exist in excitable cells, such as neurons and muscle cells, are also present in fibroblasts and may contribute to their activation (26,30). TTD is a unique calcium channel blocker with specific inhibitory effects on L-type and T-type Ca 2ϩ channels (13,32).…”

Ca2+ signaling in T lymphocytes: the interplay of the endoplasmic reticulum, mitochondria, membrane potential, and CRAC channels on transcription factor activation

“…Each state is labeled X ikj , where i (IP 3 binding site), j (activating Ca 2þ binding site) and k (inactivating Ca 2þ binding site) are equal to 0 (unoccupied binding site) or 1 (occupied binding site) [78]. the CRAC channel; 4) a description of the PMCA pump based on the experimental kinetics observed by Bautista and co-workers [26]; 5) a description of the membrane potentials and the ion channels that regulate it 6) a voltage-dependent potassium channel (Kv1.3) based on the experimental data of Dupuis et al [28]; 7) a calcium-dependent potassium channel based upon the data of Verheugen et al [29]; 8) a description of the TRPM4 channel by Gaur et al [30]; 9) a new formulation of the TRPC3 channel based on the experimental data of Rose et al [31]. ; 10) the Cl À channel based on data by Feske [8] 11) the L-type Ca 2þ channel description by Luo and Rudy [32]; and a Na þ channel description by Luo and Rudy [32].…”