Ca2+ signaling in cardiac myocytes overexpressing the α1 subunit of L-type Ca2+ channel

Long Sheng Song, António Guia, James N. Muth, Marta Rubio, Shi Qiang Wang, Rui Ping Xiao, Ira R. Josephson, Edward Lakatta, Arnold Schwartz, Heping Cheng

Research output: Contribution to journalArticle

Abstract

Voltage-gated L-type Ca2+ channels (LCCs) provide Ca2+ ingress into cardiac myocytes and play a key role in intracellular Ca2+ homeostasis and excitation-contraction coupling. We investigated the effects of a constitutive increase of LCC density on Ca2+ signaling in ventricular myocytes from 4-month-old transgenic (Tg) mice overexpressing the α1 subunit of LCC in the heart. At this age, cells were somewhat hypertrophic as reflected by a 20% increase in cell capacitance relative to those from nontransgenic (Ntg) littermates. Whole cell ICa density in Tg myocytes was elevated by 48% at 0 mV compared with the Ntg group. Single-channel analysis detected an increase in LCC density with similar conductance and gating properties. Although the overexpressed LCCs triggered an augmented SR Ca2+ release, the "gain" function of EC coupling was uncompromised, and SR Ca2+ content, diastolic cytosolic Ca2+, and unitary properties of Ca2+ sparks were unchanged. Importantly, the enhanced ICa entry and SR Ca2+ release were associated with an upregulation of the Na+-Ca2+ exchange activity (indexed by the half decay time of caffeine-elicited Ca2+ transient) by 27% and SR Ca2+ recycling by ≈35%. Western analysis detected a 53% increase in the Na+-Ca2+ exchanger expression but no change in the abundance of ryanodine receptor (RyR), SERCA2, and phospholamban. Analysis of ICa kinetics suggested that SR Ca2+ release-dependent inactivation of LCCs remains intact in Tg cells. Thus, in spite of the modest cardiac hypertrophy, the overexpressed LCCs form functional coupling with RyRs, preserving both orthograde and retrograde Ca2+ signaling between LCCs and RyRs. These results also suggest that a modest but sustained increase in Ca2+ influx triggers a coordinated remodeling of Ca2+ handling to maintain Ca2+ homeostasis.

Original languageEnglish (US)
Pages (from-to)174-181
Number of pages8
JournalCirculation Research
Volume90
Issue number2
DOIs
StatePublished - Feb 8 2002
Externally publishedYes

Fingerprint

Cardiac Myocytes
Muscle Cells
Homeostasis
Excitation Contraction Coupling
Ryanodine Receptor Calcium Release Channel
Cardiomegaly
Recycling
Caffeine
Transgenic Mice
Up-Regulation
Cell Count

Keywords

  • Ca homeostasis
  • Ca sparks
  • Cardiac hypertrophy
  • Excitation-contraction coupling
  • L-type Ca channels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Song, L. S., Guia, A., Muth, J. N., Rubio, M., Wang, S. Q., Xiao, R. P., ... Cheng, H. (2002). Ca2+ signaling in cardiac myocytes overexpressing the α1 subunit of L-type Ca2+ channel. Circulation Research, 90(2), 174-181. https://doi.org/10.1161/hh0202.103230

Ca2+ signaling in cardiac myocytes overexpressing the α1 subunit of L-type Ca2+ channel. / Song, Long Sheng; Guia, António; Muth, James N.; Rubio, Marta; Wang, Shi Qiang; Xiao, Rui Ping; Josephson, Ira R.; Lakatta, Edward; Schwartz, Arnold; Cheng, Heping.

In: Circulation Research, Vol. 90, No. 2, 08.02.2002, p. 174-181.

Research output: Contribution to journalArticle

Song, LS, Guia, A, Muth, JN, Rubio, M, Wang, SQ, Xiao, RP, Josephson, IR, Lakatta, E, Schwartz, A & Cheng, H 2002, 'Ca2+ signaling in cardiac myocytes overexpressing the α1 subunit of L-type Ca2+ channel', Circulation Research, vol. 90, no. 2, pp. 174-181. https://doi.org/10.1161/hh0202.103230
Song, Long Sheng ; Guia, António ; Muth, James N. ; Rubio, Marta ; Wang, Shi Qiang ; Xiao, Rui Ping ; Josephson, Ira R. ; Lakatta, Edward ; Schwartz, Arnold ; Cheng, Heping. / Ca2+ signaling in cardiac myocytes overexpressing the α1 subunit of L-type Ca2+ channel. In: Circulation Research. 2002 ; Vol. 90, No. 2. pp. 174-181.
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abstract = "Voltage-gated L-type Ca2+ channels (LCCs) provide Ca2+ ingress into cardiac myocytes and play a key role in intracellular Ca2+ homeostasis and excitation-contraction coupling. We investigated the effects of a constitutive increase of LCC density on Ca2+ signaling in ventricular myocytes from 4-month-old transgenic (Tg) mice overexpressing the α1 subunit of LCC in the heart. At this age, cells were somewhat hypertrophic as reflected by a 20{\%} increase in cell capacitance relative to those from nontransgenic (Ntg) littermates. Whole cell ICa density in Tg myocytes was elevated by 48{\%} at 0 mV compared with the Ntg group. Single-channel analysis detected an increase in LCC density with similar conductance and gating properties. Although the overexpressed LCCs triggered an augmented SR Ca2+ release, the {"}gain{"} function of EC coupling was uncompromised, and SR Ca2+ content, diastolic cytosolic Ca2+, and unitary properties of Ca2+ sparks were unchanged. Importantly, the enhanced ICa entry and SR Ca2+ release were associated with an upregulation of the Na+-Ca2+ exchange activity (indexed by the half decay time of caffeine-elicited Ca2+ transient) by 27{\%} and SR Ca2+ recycling by ≈35{\%}. Western analysis detected a 53{\%} increase in the Na+-Ca2+ exchanger expression but no change in the abundance of ryanodine receptor (RyR), SERCA2, and phospholamban. Analysis of ICa kinetics suggested that SR Ca2+ release-dependent inactivation of LCCs remains intact in Tg cells. Thus, in spite of the modest cardiac hypertrophy, the overexpressed LCCs form functional coupling with RyRs, preserving both orthograde and retrograde Ca2+ signaling between LCCs and RyRs. These results also suggest that a modest but sustained increase in Ca2+ influx triggers a coordinated remodeling of Ca2+ handling to maintain Ca2+ homeostasis.",
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AU - Song, Long Sheng

AU - Guia, António

AU - Muth, James N.

AU - Rubio, Marta

AU - Wang, Shi Qiang

AU - Xiao, Rui Ping

AU - Josephson, Ira R.

AU - Lakatta, Edward

AU - Schwartz, Arnold

AU - Cheng, Heping

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N2 - Voltage-gated L-type Ca2+ channels (LCCs) provide Ca2+ ingress into cardiac myocytes and play a key role in intracellular Ca2+ homeostasis and excitation-contraction coupling. We investigated the effects of a constitutive increase of LCC density on Ca2+ signaling in ventricular myocytes from 4-month-old transgenic (Tg) mice overexpressing the α1 subunit of LCC in the heart. At this age, cells were somewhat hypertrophic as reflected by a 20% increase in cell capacitance relative to those from nontransgenic (Ntg) littermates. Whole cell ICa density in Tg myocytes was elevated by 48% at 0 mV compared with the Ntg group. Single-channel analysis detected an increase in LCC density with similar conductance and gating properties. Although the overexpressed LCCs triggered an augmented SR Ca2+ release, the "gain" function of EC coupling was uncompromised, and SR Ca2+ content, diastolic cytosolic Ca2+, and unitary properties of Ca2+ sparks were unchanged. Importantly, the enhanced ICa entry and SR Ca2+ release were associated with an upregulation of the Na+-Ca2+ exchange activity (indexed by the half decay time of caffeine-elicited Ca2+ transient) by 27% and SR Ca2+ recycling by ≈35%. Western analysis detected a 53% increase in the Na+-Ca2+ exchanger expression but no change in the abundance of ryanodine receptor (RyR), SERCA2, and phospholamban. Analysis of ICa kinetics suggested that SR Ca2+ release-dependent inactivation of LCCs remains intact in Tg cells. Thus, in spite of the modest cardiac hypertrophy, the overexpressed LCCs form functional coupling with RyRs, preserving both orthograde and retrograde Ca2+ signaling between LCCs and RyRs. These results also suggest that a modest but sustained increase in Ca2+ influx triggers a coordinated remodeling of Ca2+ handling to maintain Ca2+ homeostasis.

AB - Voltage-gated L-type Ca2+ channels (LCCs) provide Ca2+ ingress into cardiac myocytes and play a key role in intracellular Ca2+ homeostasis and excitation-contraction coupling. We investigated the effects of a constitutive increase of LCC density on Ca2+ signaling in ventricular myocytes from 4-month-old transgenic (Tg) mice overexpressing the α1 subunit of LCC in the heart. At this age, cells were somewhat hypertrophic as reflected by a 20% increase in cell capacitance relative to those from nontransgenic (Ntg) littermates. Whole cell ICa density in Tg myocytes was elevated by 48% at 0 mV compared with the Ntg group. Single-channel analysis detected an increase in LCC density with similar conductance and gating properties. Although the overexpressed LCCs triggered an augmented SR Ca2+ release, the "gain" function of EC coupling was uncompromised, and SR Ca2+ content, diastolic cytosolic Ca2+, and unitary properties of Ca2+ sparks were unchanged. Importantly, the enhanced ICa entry and SR Ca2+ release were associated with an upregulation of the Na+-Ca2+ exchange activity (indexed by the half decay time of caffeine-elicited Ca2+ transient) by 27% and SR Ca2+ recycling by ≈35%. Western analysis detected a 53% increase in the Na+-Ca2+ exchanger expression but no change in the abundance of ryanodine receptor (RyR), SERCA2, and phospholamban. Analysis of ICa kinetics suggested that SR Ca2+ release-dependent inactivation of LCCs remains intact in Tg cells. Thus, in spite of the modest cardiac hypertrophy, the overexpressed LCCs form functional coupling with RyRs, preserving both orthograde and retrograde Ca2+ signaling between LCCs and RyRs. These results also suggest that a modest but sustained increase in Ca2+ influx triggers a coordinated remodeling of Ca2+ handling to maintain Ca2+ homeostasis.

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