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.
- 11325871
- action
- adrenergic,
- agents,
- aggregation,
- agonists,
- alpha-1,
- and
- aniline
- animals,
- beta,
- c,
- calcium
- calcium,
- cell
- cells,
- channel,
- channels,
- chloride,
- compounds,
- contraction,
- cross-talk,
- cultured,
- cytoplasmic
- dose-response
- drug,
- dyes,
- enzyme
- fluid,
- fluorescent
- gov't,
- immunohistochemistry,
- inhibitors,
- intracellular
- l-type,
- methacholine
- musca,
- muscarinic,
- myocardial
- myocardium,
- non-u.s.
- norepinephrine,
- nuclear,
- oligodendroglia,
- oxazoles,
- p.h.s.,
- p1,
- patch-clamp
- phospholipase
- potentials,
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