Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL-1 cells using novel recording and numerical approaches

Yaopeng Hu, Yubin Duan, Ayako Takeuchi, Lin Hai-Kurahara, Jun Ichikawa, Keizo Hiraishi, Tomohiro Numata, Hiroki Ohara, Gentaro Iribe, Michio Nakaya, Masayuki X. Mori, Satoshi Matsuoka, Genshan Ma, Ryuji Inoue

Research output: Contribution to journalArticle

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Abstract

Aims Transient receptor potential cation channel subfamily melastatin member 4 (TRPM4), a Ca 2+ -activated nonselective cation channel abundantly expressed in the heart, has been implicated in conduction block and other arrhythmic propensities associated with cardiac remodelling and injury. The present study aimed to quantitatively evaluate the arrhythmogenic potential of TRPM4. Methods and results Patch clamp and biochemical analyses were performed using expression system and an immortalized atrial cardiomyocyte cell line (HL-1), and numerical model simulation was employed. After rapid desensitization, robust reactivation of TRPM4 channels required high micromolar concentrations of Ca 2+. However, upon evaluation with a newly devised, ionomycin-permeabilized cell-attached (Iono-C/A) recording technique, submicromolar concentrations of Ca 2+ (apparent K d = ∼500 nM) were enough to activate this channel. Similar submicromolar Ca 2+ dependency was also observed with sharp electrode whole-cell recording and in experiments coexpressing TRPM4 and L-type voltage-dependent Ca 2+ channels. Numerical simulations using a number of action potential (AP) models (HL-1, Nygren, Luo-Rudy) incorporating the Ca 2+ - and voltage-dependent gating parameters of TRPM4, as assessed by Iono-C/A recording, indicated that a few-fold increase in TRPM4 activity is sufficient to delay late AP repolarization and further increases (≥ six-fold) evoke early afterdepolarization. These model predictions are consistent with electrophysiological data from angiotensin II-treated HL-1 cells in which TRPM4 expression and activity were enhanced. Conclusions These results collectively indicate that the TRPM4 channel is activated by a physiological range of Ca 2+ concentrations and its excessive activity can cause arrhythmic changes. Moreover, these results demonstrate potential utility of the first AP models incorporating TRPM4 gating for in silico assessment of arrhythmogenicity in remodelling cardiac tissue.

Original languageEnglish
Pages (from-to)1243-1255
Number of pages13
JournalCardiovascular research
Volume113
Issue number10
DOIs
Publication statusPublished - Aug 1 2017

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Action Potentials
Ionomycin
Transient Receptor Potential Channels
Patch-Clamp Techniques
Cardiac Myocytes
Angiotensin II
Computer Simulation
Cations
Electrodes
Cell Line
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL-1 cells using novel recording and numerical approaches. / Hu, Yaopeng; Duan, Yubin; Takeuchi, Ayako; Hai-Kurahara, Lin; Ichikawa, Jun; Hiraishi, Keizo; Numata, Tomohiro; Ohara, Hiroki; Iribe, Gentaro; Nakaya, Michio; Mori, Masayuki X.; Matsuoka, Satoshi; Ma, Genshan; Inoue, Ryuji.

In: Cardiovascular research, Vol. 113, No. 10, 01.08.2017, p. 1243-1255.

Research output: Contribution to journalArticle

Hu, Y, Duan, Y, Takeuchi, A, Hai-Kurahara, L, Ichikawa, J, Hiraishi, K, Numata, T, Ohara, H, Iribe, G, Nakaya, M, Mori, MX, Matsuoka, S, Ma, G & Inoue, R 2017, 'Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL-1 cells using novel recording and numerical approaches', Cardiovascular research, vol. 113, no. 10, pp. 1243-1255. https://doi.org/10.1093/cvr/cvx117
Hu, Yaopeng ; Duan, Yubin ; Takeuchi, Ayako ; Hai-Kurahara, Lin ; Ichikawa, Jun ; Hiraishi, Keizo ; Numata, Tomohiro ; Ohara, Hiroki ; Iribe, Gentaro ; Nakaya, Michio ; Mori, Masayuki X. ; Matsuoka, Satoshi ; Ma, Genshan ; Inoue, Ryuji. / Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL-1 cells using novel recording and numerical approaches. In: Cardiovascular research. 2017 ; Vol. 113, No. 10. pp. 1243-1255.
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abstract = "Aims Transient receptor potential cation channel subfamily melastatin member 4 (TRPM4), a Ca 2+ -activated nonselective cation channel abundantly expressed in the heart, has been implicated in conduction block and other arrhythmic propensities associated with cardiac remodelling and injury. The present study aimed to quantitatively evaluate the arrhythmogenic potential of TRPM4. Methods and results Patch clamp and biochemical analyses were performed using expression system and an immortalized atrial cardiomyocyte cell line (HL-1), and numerical model simulation was employed. After rapid desensitization, robust reactivation of TRPM4 channels required high micromolar concentrations of Ca 2+. However, upon evaluation with a newly devised, ionomycin-permeabilized cell-attached (Iono-C/A) recording technique, submicromolar concentrations of Ca 2+ (apparent K d = ∼500 nM) were enough to activate this channel. Similar submicromolar Ca 2+ dependency was also observed with sharp electrode whole-cell recording and in experiments coexpressing TRPM4 and L-type voltage-dependent Ca 2+ channels. Numerical simulations using a number of action potential (AP) models (HL-1, Nygren, Luo-Rudy) incorporating the Ca 2+ - and voltage-dependent gating parameters of TRPM4, as assessed by Iono-C/A recording, indicated that a few-fold increase in TRPM4 activity is sufficient to delay late AP repolarization and further increases (≥ six-fold) evoke early afterdepolarization. These model predictions are consistent with electrophysiological data from angiotensin II-treated HL-1 cells in which TRPM4 expression and activity were enhanced. Conclusions These results collectively indicate that the TRPM4 channel is activated by a physiological range of Ca 2+ concentrations and its excessive activity can cause arrhythmic changes. Moreover, these results demonstrate potential utility of the first AP models incorporating TRPM4 gating for in silico assessment of arrhythmogenicity in remodelling cardiac tissue.",
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T1 - Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL-1 cells using novel recording and numerical approaches

AU - Hu, Yaopeng

AU - Duan, Yubin

AU - Takeuchi, Ayako

AU - Hai-Kurahara, Lin

AU - Ichikawa, Jun

AU - Hiraishi, Keizo

AU - Numata, Tomohiro

AU - Ohara, Hiroki

AU - Iribe, Gentaro

AU - Nakaya, Michio

AU - Mori, Masayuki X.

AU - Matsuoka, Satoshi

AU - Ma, Genshan

AU - Inoue, Ryuji

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Aims Transient receptor potential cation channel subfamily melastatin member 4 (TRPM4), a Ca 2+ -activated nonselective cation channel abundantly expressed in the heart, has been implicated in conduction block and other arrhythmic propensities associated with cardiac remodelling and injury. The present study aimed to quantitatively evaluate the arrhythmogenic potential of TRPM4. Methods and results Patch clamp and biochemical analyses were performed using expression system and an immortalized atrial cardiomyocyte cell line (HL-1), and numerical model simulation was employed. After rapid desensitization, robust reactivation of TRPM4 channels required high micromolar concentrations of Ca 2+. However, upon evaluation with a newly devised, ionomycin-permeabilized cell-attached (Iono-C/A) recording technique, submicromolar concentrations of Ca 2+ (apparent K d = ∼500 nM) were enough to activate this channel. Similar submicromolar Ca 2+ dependency was also observed with sharp electrode whole-cell recording and in experiments coexpressing TRPM4 and L-type voltage-dependent Ca 2+ channels. Numerical simulations using a number of action potential (AP) models (HL-1, Nygren, Luo-Rudy) incorporating the Ca 2+ - and voltage-dependent gating parameters of TRPM4, as assessed by Iono-C/A recording, indicated that a few-fold increase in TRPM4 activity is sufficient to delay late AP repolarization and further increases (≥ six-fold) evoke early afterdepolarization. These model predictions are consistent with electrophysiological data from angiotensin II-treated HL-1 cells in which TRPM4 expression and activity were enhanced. Conclusions These results collectively indicate that the TRPM4 channel is activated by a physiological range of Ca 2+ concentrations and its excessive activity can cause arrhythmic changes. Moreover, these results demonstrate potential utility of the first AP models incorporating TRPM4 gating for in silico assessment of arrhythmogenicity in remodelling cardiac tissue.

AB - Aims Transient receptor potential cation channel subfamily melastatin member 4 (TRPM4), a Ca 2+ -activated nonselective cation channel abundantly expressed in the heart, has been implicated in conduction block and other arrhythmic propensities associated with cardiac remodelling and injury. The present study aimed to quantitatively evaluate the arrhythmogenic potential of TRPM4. Methods and results Patch clamp and biochemical analyses were performed using expression system and an immortalized atrial cardiomyocyte cell line (HL-1), and numerical model simulation was employed. After rapid desensitization, robust reactivation of TRPM4 channels required high micromolar concentrations of Ca 2+. However, upon evaluation with a newly devised, ionomycin-permeabilized cell-attached (Iono-C/A) recording technique, submicromolar concentrations of Ca 2+ (apparent K d = ∼500 nM) were enough to activate this channel. Similar submicromolar Ca 2+ dependency was also observed with sharp electrode whole-cell recording and in experiments coexpressing TRPM4 and L-type voltage-dependent Ca 2+ channels. Numerical simulations using a number of action potential (AP) models (HL-1, Nygren, Luo-Rudy) incorporating the Ca 2+ - and voltage-dependent gating parameters of TRPM4, as assessed by Iono-C/A recording, indicated that a few-fold increase in TRPM4 activity is sufficient to delay late AP repolarization and further increases (≥ six-fold) evoke early afterdepolarization. These model predictions are consistent with electrophysiological data from angiotensin II-treated HL-1 cells in which TRPM4 expression and activity were enhanced. Conclusions These results collectively indicate that the TRPM4 channel is activated by a physiological range of Ca 2+ concentrations and its excessive activity can cause arrhythmic changes. Moreover, these results demonstrate potential utility of the first AP models incorporating TRPM4 gating for in silico assessment of arrhythmogenicity in remodelling cardiac tissue.

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