The cardiac sarcolemmal Na-Ca exchanger (NCX) is allosterically regulated
by Ca(i) such that when Ca(i) is low, NCX current (I(NCX)) deactivates.
In this study, we used membrane potential (E(m)) and I(NCX) to control
Ca entry into and Ca efflux from intact cardiac myocytes to investigate
whether this allosteric regulation (Ca activation) occurs with Ca(i)
in the physiological range. In the absence of Ca activation, the
electrochemical effect of increasing Ca(i) would be to increase
inward I(NCX) (Ca efflux) and to decrease outward I(NCX). On the
other hand, Ca activation would increase I(NCX) in both directions.
Thus, we attributed Ca(i)-dependent increases in outward I(NCX)
to allosteric regulation. Ca activation of I(NCX) was observed in
ferret myocytes but not in wild-type mouse myocytes, suggesting that
Ca regulation of NCX may be species dependent. We also studied transgenic
mouse myocytes overexpressing either normal canine NCX or this same
canine NCX lacking Ca regulation (Delta680-685). Animals with the
normal canine NCX transgene showed Ca activation, whereas animals
with the mutant transgene did not, confirming the role of this region
in the process. In native ferret cells and in mice with expressed
canine NCX, allosteric regulation by Ca occurs under physiological
conditions (K(mCaAct) = 125 +/- 16 nM SEM approximately resting Ca(i)).
This, along with the observation that no delay was observed between
measured Ca(i) and activation of I(NCX) under our conditions, suggests
that beat to beat changes in NCX function can occur in vivo. These
changes in the I(NCX) activation state may influence SR Ca load and
resting Ca(i), helping to fine tune Ca influx and efflux from cells
under both normal and pathophysiological conditions. Our failure
to observe Ca activation in mouse myocytes may be due to either the
extent of Ca regulation or to a difference in K(mCaAct) from other
species. Model predictions for Ca activation, on which our estimates
of K(mCaAct) are based, confirm that Ca activation strongly influences
outward I(NCX), explaining why it increases rather than declines
with increasing Ca(i).
%0 Journal Article
%1 Webe_2001_119
%A Weber, C. R.
%A Ginsburg, K. S.
%A Philipson, K. D.
%A Shannon, T. R.
%A Bers, D. M.
%D 2001
%J J. Gen. Physiol.
%K 11158165 ATPase, Action Adrenergic Allosteric Animals, Biological Biological, Caffeine, Calcium Calcium, Cardiac, Cardiovascular, Cell Cells, Channels, Computer Congestive, Contraction, Cultured, Cytosol, Diastole, Dogs, Electric Exchanger, Failure, Ferrets, Fibers, Gov't, Heart Heart, Humans, Ion Isoproterenol, Kinetics, Membrane Membrane, Mice, Models, Muscle Mutagenesis, Myocardial Myocardium, Myocytes, Nickel, Non-U.S. P.H.S., Potentials, Rabbits, Regulation, Research Reticulum, Sarcoplasmic Signaling, Simulation, Sodium-Calcium Stimulation, Support, Tetracaine, Transport, U.S. Ventricles, beta-Agonists, {C}a$^{2+}$-Transporting
%N 2
%P 119--131
%T Allosteric regulation of Na/Ca exchange current by cytosolic Ca in
intact cardiac myocytes.
%U http://www.jgp.org/cgi/content/full/117/2/119
%V 117
%X The cardiac sarcolemmal Na-Ca exchanger (NCX) is allosterically regulated
by Ca(i) such that when Ca(i) is low, NCX current (I(NCX)) deactivates.
In this study, we used membrane potential (E(m)) and I(NCX) to control
Ca entry into and Ca efflux from intact cardiac myocytes to investigate
whether this allosteric regulation (Ca activation) occurs with Ca(i)
in the physiological range. In the absence of Ca activation, the
electrochemical effect of increasing Ca(i) would be to increase
inward I(NCX) (Ca efflux) and to decrease outward I(NCX). On the
other hand, Ca activation would increase I(NCX) in both directions.
Thus, we attributed Ca(i)-dependent increases in outward I(NCX)
to allosteric regulation. Ca activation of I(NCX) was observed in
ferret myocytes but not in wild-type mouse myocytes, suggesting that
Ca regulation of NCX may be species dependent. We also studied transgenic
mouse myocytes overexpressing either normal canine NCX or this same
canine NCX lacking Ca regulation (Delta680-685). Animals with the
normal canine NCX transgene showed Ca activation, whereas animals
with the mutant transgene did not, confirming the role of this region
in the process. In native ferret cells and in mice with expressed
canine NCX, allosteric regulation by Ca occurs under physiological
conditions (K(mCaAct) = 125 +/- 16 nM SEM approximately resting Ca(i)).
This, along with the observation that no delay was observed between
measured Ca(i) and activation of I(NCX) under our conditions, suggests
that beat to beat changes in NCX function can occur in vivo. These
changes in the I(NCX) activation state may influence SR Ca load and
resting Ca(i), helping to fine tune Ca influx and efflux from cells
under both normal and pathophysiological conditions. Our failure
to observe Ca activation in mouse myocytes may be due to either the
extent of Ca regulation or to a difference in K(mCaAct) from other
species. Model predictions for Ca activation, on which our estimates
of K(mCaAct) are based, confirm that Ca activation strongly influences
outward I(NCX), explaining why it increases rather than declines
with increasing Ca(i).
@article{Webe_2001_119,
abstract = {The cardiac sarcolemmal Na-Ca exchanger (NCX) is allosterically regulated
by [Ca](i) such that when [Ca](i) is low, NCX current (I(NCX)) deactivates.
In this study, we used membrane potential (E(m)) and I(NCX) to control
Ca entry into and Ca efflux from intact cardiac myocytes to investigate
whether this allosteric regulation (Ca activation) occurs with [Ca](i)
in the physiological range. In the absence of Ca activation, the
electrochemical effect of increasing [Ca](i) would be to increase
inward I(NCX) (Ca efflux) and to decrease outward I(NCX). On the
other hand, Ca activation would increase I(NCX) in both directions.
Thus, we attributed [Ca](i)-dependent increases in outward I(NCX)
to allosteric regulation. Ca activation of I(NCX) was observed in
ferret myocytes but not in wild-type mouse myocytes, suggesting that
Ca regulation of NCX may be species dependent. We also studied transgenic
mouse myocytes overexpressing either normal canine NCX or this same
canine NCX lacking Ca regulation (Delta680-685). Animals with the
normal canine NCX transgene showed Ca activation, whereas animals
with the mutant transgene did not, confirming the role of this region
in the process. In native ferret cells and in mice with expressed
canine NCX, allosteric regulation by Ca occurs under physiological
conditions (K(mCaAct) = 125 +/- 16 nM SEM approximately resting [Ca](i)).
This, along with the observation that no delay was observed between
measured [Ca](i) and activation of I(NCX) under our conditions, suggests
that beat to beat changes in NCX function can occur in vivo. These
changes in the I(NCX) activation state may influence SR Ca load and
resting [Ca](i), helping to fine tune Ca influx and efflux from cells
under both normal and pathophysiological conditions. Our failure
to observe Ca activation in mouse myocytes may be due to either the
extent of Ca regulation or to a difference in K(mCaAct) from other
species. Model predictions for Ca activation, on which our estimates
of K(mCaAct) are based, confirm that Ca activation strongly influences
outward I(NCX), explaining why it increases rather than declines
with increasing [Ca](i).},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Weber, C. R. and Ginsburg, K. S. and Philipson, K. D. and Shannon, T. R. and Bers, D. M.},
biburl = {https://www.bibsonomy.org/bibtex/29a58a9803506540254648aa1e40a6858/hake},
description = {The whole bibliography file I use.},
file = {Webe_2001_119.pdf:Webe_2001_119.pdf:PDF},
interhash = {ee0455da076bc147a506645e931f2306},
intrahash = {9a58a9803506540254648aa1e40a6858},
journal = {J. Gen. Physiol.},
key = 103,
keywords = {11158165 ATPase, Action Adrenergic Allosteric Animals, Biological Biological, Caffeine, Calcium Calcium, Cardiac, Cardiovascular, Cell Cells, Channels, Computer Congestive, Contraction, Cultured, Cytosol, Diastole, Dogs, Electric Exchanger, Failure, Ferrets, Fibers, Gov't, Heart Heart, Humans, Ion Isoproterenol, Kinetics, Membrane Membrane, Mice, Models, Muscle Mutagenesis, Myocardial Myocardium, Myocytes, Nickel, Non-U.S. P.H.S., Potentials, Rabbits, Regulation, Research Reticulum, Sarcoplasmic Signaling, Simulation, Sodium-Calcium Stimulation, Support, Tetracaine, Transport, U.S. Ventricles, beta-Agonists, {C}a$^{2+}$-Transporting},
month = Feb,
number = 2,
pages = {119--131},
pmid = {11158165},
timestamp = {2009-06-03T11:21:36.000+0200},
title = {Allosteric regulation of Na/Ca exchange current by cytosolic Ca in
intact cardiac myocytes.},
url = {http://www.jgp.org/cgi/content/full/117/2/119},
volume = 117,
year = 2001
}