title: beta-Adrenergic stimulation synchronizes intracellular Ca(2+) release during excitation-contraction coupling in cardiac myocytes.
abstract: To elucidate microscopic mechanisms underlying the modulation of cardiac excitation-contraction (EC) coupling by beta-adrenergic receptor (beta-AR) stimulation, we examined local Ca(2+) release function, ie, Ca(2+) spikes at individual transverse tubule-sarcoplasmic reticulum (T-SR) junctions, using confocal microscopy and our recently developed technique for release flux measurement. beta-AR stimulation by norepinephrine plus an alpha(1)-adrenergic blocker, prazosin, increased the amplitude of SR Ca(2+) release flux (J(SR)), its running integral (integralJ(SR)), and L-type Ca(2+) channel current (I(Ca)), and it shifted their bell-shaped voltage dependence leftward by approximately 10 mV, with the relative effects ranking I(Ca)> J(SR)>integralJ(SR). Confocal imaging revealed that the bell-shaped voltage dependence of SR Ca(2+) release is attributable to a graded recruitment of T-SR junctions as well as to changes in Ca(2+) spike amplitudes. beta-AR stimulation increased the fractional T-SR junctions that fired Ca(2+) spikes and augmented Ca(2+) spike amplitudes, without altering the SR Ca(2+) load, suggesting that more release units were activated synchronously among and within T-SR junctions. Moreover, beta-AR stimulation decreased the latency and temporal dispersion of Ca(2+) spike occurrence at a given voltage, delivering most of the Ca(2+) at the onset of depolarization rather than spreading it out throughout depolarization. Because the synchrony of Ca(2+) spikes affects Ca(2+) delivery per unit of time to contractile myofilaments, and because the myofilaments display a steep Ca(2+) dependence, our data suggest that synchronization of SR Ca(2+) release represents a heretofore unappreciated mechanism of beta-AR modulation of cardiac inotropy.
authors.affiliation: Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Md, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Song
authors.forename: S Q
authors.initials: SQ
authors.lastname: Wang
authors.forename: R P
authors.initials: RP
authors.lastname: Xiao
authors.forename: H
authors.initials: H
authors.lastname: Spurgeon
authors.forename: E G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: H
authors.initials: H
authors.lastname: Cheng
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002469:Cell Separation; D005456:Fluorescent Dyes; D007424:Intracellular Fluid / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D020746:Calcium Channels, L-Type; D005456:Fluorescent Dyes; D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D014662:Vasoconstrictor Agents; D002118:Calcium; D009638:Norepinephrine