Mg2+, an important constituent of the intracellular milieu in cardiac
myocytes, is known to inhibit ryanodine receptor (RyR) Ca$^2+$
release channels by competing with Ca$^2+$ at the cytosolic activation
sites of the channel. However, the significance of this competition
for local, dynamic Ca$^2+$-signaling processes thought to govern
cardiac excitation-contraction (EC) coupling remains largely unknown.
In the present study, Ca$^2+$ stimuli of different waveforms
(i.e., sustained and brief) were generated by photolysis of the caged
Ca$^2+$ compound nitrophenyl (NP)-EGTA. The evoked RyR activity
was measured in planar lipid bilayers in the presence of 0.6-1.3
mM free Mg2+ at the background of 3 mM total ATP in the presence
or absence of 1 mM luminal Ca$^2+$. Mg2+ dramatically slowed
the rate of activation of RyRs in response to sustained (> or =10-ms)
elevations in Ca$^2+$ concentration. Paradoxically, Mg2+ had
no measurable impact on the kinetics of the RyR response induced
by physiologically relevant, brief (<1-ms) Ca$^2+$ stimuli. Instead,
the changes in activation rate observed with sustained stimuli were
translated into a drastic reduction in the probability of responses.
Luminal Ca$^2+$ did not affect the peak open probability or the
probability of responses to brief Ca$^2+$ signals; however, it
slowed the transition to steady state and increased the steady-state
open probability of the channel. Our results indicate that Mg2+ is
a critical physiological determinant of the dynamic behavior of the
RyR channel, which is expected to profoundly influence the fidelity
of coupling between L-type Ca$^2+$ channels and RyRs in heart
cells.
Institute of Molecular Physiology and Genetics, Slovak Academy of
Sciences, Vl�rska 5, 833 34 Bratislava, Slovak Republic. alexandra.zahradnikova@savba.sk
%0 Journal Article
%1 Zahr_2003_C1059
%A Zahradn�kov�, A.
%A Dura, M.
%A Gy�rke, I.
%A Escobar, A. L.
%A Zahradn�k, I.
%A Gy�rke, S.
%D 2003
%J Am. J. Physiol. Cell Physiol.
%K Animals; Calcium Calcium; Cardiac; Cells, Channel Cultured; Dogs; Dose-Response Drug; Magnesium; Myocytes, Receptor Relationship, Release Ryanodine
%N 5
%P C1059--C1070
%R 10.1152/ajpcell.00118.2003
%T Regulation of dynamic behavior of cardiac ryanodine receptor by Mg2+
under simulated physiological conditions.
%U http://ajpcell.physiology.org/cgi/content/full/285/5/C1059
%V 285
%X Mg2+, an important constituent of the intracellular milieu in cardiac
myocytes, is known to inhibit ryanodine receptor (RyR) Ca$^2+$
release channels by competing with Ca$^2+$ at the cytosolic activation
sites of the channel. However, the significance of this competition
for local, dynamic Ca$^2+$-signaling processes thought to govern
cardiac excitation-contraction (EC) coupling remains largely unknown.
In the present study, Ca$^2+$ stimuli of different waveforms
(i.e., sustained and brief) were generated by photolysis of the caged
Ca$^2+$ compound nitrophenyl (NP)-EGTA. The evoked RyR activity
was measured in planar lipid bilayers in the presence of 0.6-1.3
mM free Mg2+ at the background of 3 mM total ATP in the presence
or absence of 1 mM luminal Ca$^2+$. Mg2+ dramatically slowed
the rate of activation of RyRs in response to sustained (> or =10-ms)
elevations in Ca$^2+$ concentration. Paradoxically, Mg2+ had
no measurable impact on the kinetics of the RyR response induced
by physiologically relevant, brief (<1-ms) Ca$^2+$ stimuli. Instead,
the changes in activation rate observed with sustained stimuli were
translated into a drastic reduction in the probability of responses.
Luminal Ca$^2+$ did not affect the peak open probability or the
probability of responses to brief Ca$^2+$ signals; however, it
slowed the transition to steady state and increased the steady-state
open probability of the channel. Our results indicate that Mg2+ is
a critical physiological determinant of the dynamic behavior of the
RyR channel, which is expected to profoundly influence the fidelity
of coupling between L-type Ca$^2+$ channels and RyRs in heart
cells.
@article{Zahr_2003_C1059,
abstract = {Mg2+, an important constituent of the intracellular milieu in cardiac
myocytes, is known to inhibit ryanodine receptor (RyR) {C}a$^{2+}$
release channels by competing with {C}a$^{2+}$ at the cytosolic activation
sites of the channel. However, the significance of this competition
for local, dynamic {C}a$^{2+}$-signaling processes thought to govern
cardiac excitation-contraction (EC) coupling remains largely unknown.
In the present study, {C}a$^{2+}$ stimuli of different waveforms
(i.e., sustained and brief) were generated by photolysis of the caged
{C}a$^{2+}$ compound nitrophenyl (NP)-EGTA. The evoked RyR activity
was measured in planar lipid bilayers in the presence of 0.6-1.3
mM free Mg2+ at the background of 3 mM total ATP in the presence
or absence of 1 mM luminal {C}a$^{2+}$. Mg2+ dramatically slowed
the rate of activation of RyRs in response to sustained (> or =10-ms)
elevations in {C}a$^{2+}$ concentration. Paradoxically, Mg2+ had
no measurable impact on the kinetics of the RyR response induced
by physiologically relevant, brief (<1-ms) {C}a$^{2+}$ stimuli. Instead,
the changes in activation rate observed with sustained stimuli were
translated into a drastic reduction in the probability of responses.
Luminal {C}a$^{2+}$ did not affect the peak open probability or the
probability of responses to brief {C}a$^{2+}$ signals; however, it
slowed the transition to steady state and increased the steady-state
open probability of the channel. Our results indicate that Mg2+ is
a critical physiological determinant of the dynamic behavior of the
RyR channel, which is expected to profoundly influence the fidelity
of coupling between L-type {C}a$^{2+}$ channels and RyRs in heart
cells.},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Zahradn�kov�, A. and Dura, M. and Gy�rke, I. and Escobar, A. L. and Zahradn�k, I. and Gy�rke, S.},
biburl = {https://www.bibsonomy.org/bibtex/25626b6a3b6ca2ac617f9a5ca86a3b076/hake},
description = {The whole bibliography file I use.},
doi = {10.1152/ajpcell.00118.2003},
file = {Zahr_2003_C1059.pdf:Zahr_2003_C1059.pdf:PDF},
institution = {Institute of Molecular Physiology and Genetics, Slovak Academy of
Sciences, Vl�rska 5, 833 34 Bratislava, Slovak Republic. alexandra.zahradnikova@savba.sk},
interhash = {f8889acf97c576ac5a2b058b501943b7},
intrahash = {5626b6a3b6ca2ac617f9a5ca86a3b076},
journal = {Am. J. Physiol. Cell Physiol.},
keywords = {Animals; Calcium Calcium; Cardiac; Cells, Channel Cultured; Dogs; Dose-Response Drug; Magnesium; Myocytes, Receptor Relationship, Release Ryanodine},
month = Nov,
number = 5,
pages = {C1059--C1070},
pdf = {Zahr_2003_C1059.pdf},
pii = {00118.2003},
pmid = {12839831},
timestamp = {2009-06-03T11:21:38.000+0200},
title = {Regulation of dynamic behavior of cardiac ryanodine receptor by Mg2+
under simulated physiological conditions.},
url = {http://ajpcell.physiology.org/cgi/content/full/285/5/C1059},
volume = 285,
year = 2003
}