INTRACELLULAR CALCIUM REGULATION--CARDIAC MUSCLE CELLS

Project Details

Description

DESCRIPTION: The aim of this proposal is to determine what events, at
the subcellular level, underlie excitation-contraction (E-C) coupling
in cardiac muscle cells. Recent experiments have supported a Ca2+-
induced Ca2+ release (CICR) mechanism in which "localized" increases of
cytosolic Ca2+ concentration ((Ca2+)i), dependent on Ca influx through
sarcolemmal (SL) Ca channels (or the Na/Ca exchanger) during an action
potential, trigger the release of Ca2+ sequestered in the sarcoplasmic
reticulum (SR).

Paradoxically, the clearest examples of the CICR mechanism are observed
during periods of cellular Ca2+ loading when spontaneous, propagated
increases in (Ca2+)i occur without an action potential and, therefore,
without "localized" increases in (Ca2+)i due to Ca2+ influx. This
dichotomy of E-C coupling behavior in cardiac myocytes clearly points
out that many aspects of the CICR mechanism are not understood at this
time. In this project, the applicant will test the hypothesis that
"localized" increases in (Ca2+)i is dependent on the degree cellular
Ca2+ loading and the organization of SL and SR Ca channels involved in
E-C coupling. To test this hypothesis, experiments have been designed
to address the following specific questions: (1) how does increased
cytosolic Ca2+ buffering affect E-C coupling; (2) can SL Ca channel
blockers change the relationship between "localized" increases in
(Ca2+)i due to Ca2+ influx and SR Ca2+ release; (3) how does cellular
Ca2+ loading affect E-C coupling; (4) does E-C coupling behave
differently in atrial and ventricular myocytes? To answer these
questions, experiments will be performed on single cardiac myocytes
voltage clamped with low resistance patch electrodes while (Ca2+)i is
simultaneously measured with fluorescent Ca indicators using
spectrofluorimetic and confocal microscopy techniques.
StatusFinished
Effective start/end date8/15/9511/30/01

Funding

  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute

ASJC

  • Cardiology and Cardiovascular Medicine

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