title: Ca(2+) signaling in cardiac myocytes overexpressing the alpha(1) subunit of L-type Ca(2+) channel.
abstract: Voltage-gated L-type Ca(2+) channels (LCCs) provide Ca(2+) ingress into cardiac myocytes and play a key role in intracellular Ca(2+) homeostasis and excitation-contraction coupling. We investigated the effects of a constitutive increase of LCC density on Ca(2+) signaling in ventricular myocytes from 4-month-old transgenic (Tg) mice overexpressing the alpha(1) 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 I(Ca) 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 Ca(2+) release, the "gain" function of EC coupling was uncompromised, and SR Ca(2+) content, diastolic cytosolic Ca(2+), and unitary properties of Ca(2+) sparks were unchanged. Importantly, the enhanced I(Ca) entry and SR Ca(2+) release were associated with an upregulation of the Na(+)-Ca(2+) exchange activity (indexed by the half decay time of caffeine-elicited Ca(2+) transient) by 27% and SR Ca(2+) recycling by approximately 35%. Western analysis detected a 53% increase in the Na(+)-Ca(2+) exchanger expression but no change in the abundance of ryanodine receptor (RyR), SERCA2, and phospholamban. Analysis of I(Ca) kinetics suggested that SR Ca(2+) 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 Ca(2+) signaling between LCCs and RyRs. These results also suggest that a modest but sustained increase in Ca(2+) influx triggers a coordinated remodeling of Ca(2+) handling to maintain Ca(2+) homeostasis.
authors.affiliation: Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
authors.forename: António
authors.initials: A
authors.lastname: Guia
authors.forename: James N
authors.initials: JN
authors.lastname: Muth
authors.forename: Marta
authors.initials: M
authors.lastname: Rubio
authors.forename: Shi-Qiang
authors.initials: SQ
authors.lastname: Wang
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
authors.forename: Ira R
authors.initials: IR
authors.lastname: Josephson
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: Arnold
authors.initials: A
authors.lastname: Schwartz
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000096:biosynthesis* / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002469:Cell Separation; D003600:Cytosol / Q000378:metabolism; D006706:Homeostasis; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002110:Caffeine; D002118:Calcium; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D021122:Protein Subunits; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban; C506947:Atp2a2 protein, mouse