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TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1.

Doleschal B, Primessnig U, Wölkart G, Wolf S, Schernthaner M, Lichtenegger M, Glasnov TN, Kappe CO, Mayer B, Antoons G, Heinzel F, Poteser M, Groschner K - Cardiovasc. Res. (2015)

Bottom Line: GSK1702934A induced a transient, non-selective conductance and prolonged action potentials in TRPC3-overexpressing myocytes but lacked significant electrophysiological effects in wild-type myocytes.Excessive activation of TRPC3 is associated with transient cellular Ca2+ overload, spatial uncoupling between TRPC3 and NCX1, and arrhythmogenesis.We propose TRPC3-NCX micro/nanodomain communication as determinant of cardiac contractility and susceptibility to arrhythmogenic stimuli.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.

No MeSH data available.


Related in: MedlinePlus

Arrhythmic activity in cardiomyocytes in response to TRPC3 activation requires rise of intracellular Ca2+ and NCX1 function. Action potentials were recorded from single myocytes upon intracellular current injection (1–2 nA amplitude, 2–4 ms duration) at a pacing cycle length of 2 s.28 (A) Continuous AP recordings displayed prominent arrhythmic afterdepolarizations (EADs and DADs) in TRPC3-TG myocytes during GSK infusion; WT (left panel), TRPC3-TG (right panel). (B) Frequency of arrhythmic events (number of EADs and DADs during 10 min application of GSK). Both EADs (4.7 ± 1.79 TG; n = 15; N = 3 vs. 0.3 ± 0.3 WT; n = 17; N = 4; P < 0.05) and DADs (10.75 ± 3.08 TG vs. 3.63 ± 1.32 WT; P < 0.05) were significantly increased in TRPC3-TG myocytes. Statistical significance analysed by Wilcoxon–Mann–Whitney test. (C) Incidence of afterdepolarizations (AD, left), delayed ADs (DAD, centre), and early ADs (EAD, right): WT compared with TRPC3-TG cells ±  buffered to diastolic levels by 11 mM EGTA (n = 10; N = 3) or in the presence of the NCX1 inhibitor DCB (10 µM; n = 8; N = 3). Black bars represent population of cells displaying arrhythmic events during 10 min (n > 3). * indicates statistical significance (P < 0.05) in comparison to WT conditions, sharp (#) indicates (P < 0.05) in comparison to untreated TRPC3-TG myocytes. Statistical significance analysed by Fisher’s exact test.
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CVV022F3: Arrhythmic activity in cardiomyocytes in response to TRPC3 activation requires rise of intracellular Ca2+ and NCX1 function. Action potentials were recorded from single myocytes upon intracellular current injection (1–2 nA amplitude, 2–4 ms duration) at a pacing cycle length of 2 s.28 (A) Continuous AP recordings displayed prominent arrhythmic afterdepolarizations (EADs and DADs) in TRPC3-TG myocytes during GSK infusion; WT (left panel), TRPC3-TG (right panel). (B) Frequency of arrhythmic events (number of EADs and DADs during 10 min application of GSK). Both EADs (4.7 ± 1.79 TG; n = 15; N = 3 vs. 0.3 ± 0.3 WT; n = 17; N = 4; P < 0.05) and DADs (10.75 ± 3.08 TG vs. 3.63 ± 1.32 WT; P < 0.05) were significantly increased in TRPC3-TG myocytes. Statistical significance analysed by Wilcoxon–Mann–Whitney test. (C) Incidence of afterdepolarizations (AD, left), delayed ADs (DAD, centre), and early ADs (EAD, right): WT compared with TRPC3-TG cells ± buffered to diastolic levels by 11 mM EGTA (n = 10; N = 3) or in the presence of the NCX1 inhibitor DCB (10 µM; n = 8; N = 3). Black bars represent population of cells displaying arrhythmic events during 10 min (n > 3). * indicates statistical significance (P < 0.05) in comparison to WT conditions, sharp (#) indicates (P < 0.05) in comparison to untreated TRPC3-TG myocytes. Statistical significance analysed by Fisher’s exact test.

Mentions: The arrhythmogenic action of GSK was clearly evident from AP recording in isolated myocytes. Analysis of 10 min continuous recordings during GSK perfusion revealed a higher incidence of arrhythmic depolarizations (early and late afterdepolarizations) in TRPC3-TG compared with WT cardiomyocytes (Figure 3A and B). It is of note that the effects of AngII in isolated TRPC3-TG cardiomyocytes resembled that of GSK in terms of changes in AP morphology (see Supplementary material online, Figure S4D).Figure 3


TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1.

Doleschal B, Primessnig U, Wölkart G, Wolf S, Schernthaner M, Lichtenegger M, Glasnov TN, Kappe CO, Mayer B, Antoons G, Heinzel F, Poteser M, Groschner K - Cardiovasc. Res. (2015)

Arrhythmic activity in cardiomyocytes in response to TRPC3 activation requires rise of intracellular Ca2+ and NCX1 function. Action potentials were recorded from single myocytes upon intracellular current injection (1–2 nA amplitude, 2–4 ms duration) at a pacing cycle length of 2 s.28 (A) Continuous AP recordings displayed prominent arrhythmic afterdepolarizations (EADs and DADs) in TRPC3-TG myocytes during GSK infusion; WT (left panel), TRPC3-TG (right panel). (B) Frequency of arrhythmic events (number of EADs and DADs during 10 min application of GSK). Both EADs (4.7 ± 1.79 TG; n = 15; N = 3 vs. 0.3 ± 0.3 WT; n = 17; N = 4; P < 0.05) and DADs (10.75 ± 3.08 TG vs. 3.63 ± 1.32 WT; P < 0.05) were significantly increased in TRPC3-TG myocytes. Statistical significance analysed by Wilcoxon–Mann–Whitney test. (C) Incidence of afterdepolarizations (AD, left), delayed ADs (DAD, centre), and early ADs (EAD, right): WT compared with TRPC3-TG cells ±  buffered to diastolic levels by 11 mM EGTA (n = 10; N = 3) or in the presence of the NCX1 inhibitor DCB (10 µM; n = 8; N = 3). Black bars represent population of cells displaying arrhythmic events during 10 min (n > 3). * indicates statistical significance (P < 0.05) in comparison to WT conditions, sharp (#) indicates (P < 0.05) in comparison to untreated TRPC3-TG myocytes. Statistical significance analysed by Fisher’s exact test.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4362401&req=5

CVV022F3: Arrhythmic activity in cardiomyocytes in response to TRPC3 activation requires rise of intracellular Ca2+ and NCX1 function. Action potentials were recorded from single myocytes upon intracellular current injection (1–2 nA amplitude, 2–4 ms duration) at a pacing cycle length of 2 s.28 (A) Continuous AP recordings displayed prominent arrhythmic afterdepolarizations (EADs and DADs) in TRPC3-TG myocytes during GSK infusion; WT (left panel), TRPC3-TG (right panel). (B) Frequency of arrhythmic events (number of EADs and DADs during 10 min application of GSK). Both EADs (4.7 ± 1.79 TG; n = 15; N = 3 vs. 0.3 ± 0.3 WT; n = 17; N = 4; P < 0.05) and DADs (10.75 ± 3.08 TG vs. 3.63 ± 1.32 WT; P < 0.05) were significantly increased in TRPC3-TG myocytes. Statistical significance analysed by Wilcoxon–Mann–Whitney test. (C) Incidence of afterdepolarizations (AD, left), delayed ADs (DAD, centre), and early ADs (EAD, right): WT compared with TRPC3-TG cells ± buffered to diastolic levels by 11 mM EGTA (n = 10; N = 3) or in the presence of the NCX1 inhibitor DCB (10 µM; n = 8; N = 3). Black bars represent population of cells displaying arrhythmic events during 10 min (n > 3). * indicates statistical significance (P < 0.05) in comparison to WT conditions, sharp (#) indicates (P < 0.05) in comparison to untreated TRPC3-TG myocytes. Statistical significance analysed by Fisher’s exact test.
Mentions: The arrhythmogenic action of GSK was clearly evident from AP recording in isolated myocytes. Analysis of 10 min continuous recordings during GSK perfusion revealed a higher incidence of arrhythmic depolarizations (early and late afterdepolarizations) in TRPC3-TG compared with WT cardiomyocytes (Figure 3A and B). It is of note that the effects of AngII in isolated TRPC3-TG cardiomyocytes resembled that of GSK in terms of changes in AP morphology (see Supplementary material online, Figure S4D).Figure 3

Bottom Line: GSK1702934A induced a transient, non-selective conductance and prolonged action potentials in TRPC3-overexpressing myocytes but lacked significant electrophysiological effects in wild-type myocytes.Excessive activation of TRPC3 is associated with transient cellular Ca2+ overload, spatial uncoupling between TRPC3 and NCX1, and arrhythmogenesis.We propose TRPC3-NCX micro/nanodomain communication as determinant of cardiac contractility and susceptibility to arrhythmogenic stimuli.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.

No MeSH data available.


Related in: MedlinePlus