The free Ca$^2+$ in endoplasmic/sarcoplasmic reticulum Ca$^2+$
stores regulates excitability of Ca$^2+$ release by stimulating
the Ca$^2+$ release channels. Just how the stored Ca$^2+$
regulates activation of these channels is still disputed. One proposal
attributes luminal Ca$^2+$-activation to luminal facing regulatory
sites, whereas another envisages Ca$^2+$ permeation to cytoplasmic
sites. This study develops a unified model for luminal Ca$^2+$
activation for single cardiac ryanodine receptors (RyR2) and RyRs
in coupled clusters in artificial lipid bilayers. It is shown that
luminal regulation of RyR2 involves three modes of action associated
with Ca$^2+$ sensors in different parts of the molecule; a luminal
activation site (L-site, 60 microM affinity), a cytoplasmic activation
site (A-site, 0.9 microM affinity), and a novel cytoplasmic inactivation
site (I2-site, 1.2 microM affinity). RyR activation by luminal Ca$^2+$
is demonstrated to occur by a multistep process dubbed luminal-triggered
Ca$^2+$ feedthrough. Ca$^2+$ binding to the L-site initiates
brief openings (1 ms duration at 1-10 s(-1)) allowing luminal Ca$^2+$
to access the A-site, producing up to 30-fold prolongation of openings.
The model explains a broad data set, reconciles previous conflicting
observations and provides a foundation for understanding the action
of pharmacological agents, RyR-associated proteins, and RyR2 mutations
on a range of Ca$^2+$-mediated physiological and pathological
processes.
School of Biomedical Sciences, University of Newcastle and Hunter
Medical Research Institute, Callaghan, New South Wales, Australia.
derek.laver@newcastle.edu.au
%0 Journal Article
%1 Lave_2007_3541
%A Laver, Derek R
%D 2007
%J Biophys. J.
%K Bilayers; Calcium Calcium; Channel Chemical; Computer Cytosol; Gating; Ion Lipid Models, Receptor Release Ryanodine Simulation;
%N 10
%P 3541--3555
%R 10.1529/biophysj.106.099028
%T Ca$^2+$ stores regulate ryanodine receptor Ca$^2+$ release
channels via luminal and cytosolic Ca$^2+$ sites.
%U http://dx.doi.org/10.1529/biophysj.106.099028
%V 92
%X The free Ca$^2+$ in endoplasmic/sarcoplasmic reticulum Ca$^2+$
stores regulates excitability of Ca$^2+$ release by stimulating
the Ca$^2+$ release channels. Just how the stored Ca$^2+$
regulates activation of these channels is still disputed. One proposal
attributes luminal Ca$^2+$-activation to luminal facing regulatory
sites, whereas another envisages Ca$^2+$ permeation to cytoplasmic
sites. This study develops a unified model for luminal Ca$^2+$
activation for single cardiac ryanodine receptors (RyR2) and RyRs
in coupled clusters in artificial lipid bilayers. It is shown that
luminal regulation of RyR2 involves three modes of action associated
with Ca$^2+$ sensors in different parts of the molecule; a luminal
activation site (L-site, 60 microM affinity), a cytoplasmic activation
site (A-site, 0.9 microM affinity), and a novel cytoplasmic inactivation
site (I2-site, 1.2 microM affinity). RyR activation by luminal Ca$^2+$
is demonstrated to occur by a multistep process dubbed luminal-triggered
Ca$^2+$ feedthrough. Ca$^2+$ binding to the L-site initiates
brief openings (1 ms duration at 1-10 s(-1)) allowing luminal Ca$^2+$
to access the A-site, producing up to 30-fold prolongation of openings.
The model explains a broad data set, reconciles previous conflicting
observations and provides a foundation for understanding the action
of pharmacological agents, RyR-associated proteins, and RyR2 mutations
on a range of Ca$^2+$-mediated physiological and pathological
processes.
@article{Lave_2007_3541,
abstract = {The free [{C}a$^{2+}$] in endoplasmic/sarcoplasmic reticulum {C}a$^{2+}$
stores regulates excitability of {C}a$^{2+}$ release by stimulating
the {C}a$^{2+}$ release channels. Just how the stored {C}a$^{2+}$
regulates activation of these channels is still disputed. One proposal
attributes luminal {C}a$^{2+}$-activation to luminal facing regulatory
sites, whereas another envisages {C}a$^{2+}$ permeation to cytoplasmic
sites. This study develops a unified model for luminal {C}a$^{2+}$
activation for single cardiac ryanodine receptors (RyR2) and RyRs
in coupled clusters in artificial lipid bilayers. It is shown that
luminal regulation of RyR2 involves three modes of action associated
with {C}a$^{2+}$ sensors in different parts of the molecule; a luminal
activation site (L-site, 60 microM affinity), a cytoplasmic activation
site (A-site, 0.9 microM affinity), and a novel cytoplasmic inactivation
site (I2-site, 1.2 microM affinity). RyR activation by luminal {C}a$^{2+}$
is demonstrated to occur by a multistep process dubbed luminal-triggered
{C}a$^{2+}$ feedthrough. {C}a$^{2+}$ binding to the L-site initiates
brief openings (1 ms duration at 1-10 s(-1)) allowing luminal {C}a$^{2+}$
to access the A-site, producing up to 30-fold prolongation of openings.
The model explains a broad data set, reconciles previous conflicting
observations and provides a foundation for understanding the action
of pharmacological agents, RyR-associated proteins, and RyR2 mutations
on a range of {C}a$^{2+}$-mediated physiological and pathological
processes.},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Laver, Derek R},
biburl = {https://www.bibsonomy.org/bibtex/290346541318e6f510275976872684a3e/hake},
description = {The whole bibliography file I use.},
doi = {10.1529/biophysj.106.099028},
file = {Lave_2007_3541.pdf:Lave_2007_3541.pdf:PDF},
institution = {School of Biomedical Sciences, University of Newcastle and Hunter
Medical Research Institute, Callaghan, New South Wales, Australia.
derek.laver@newcastle.edu.au},
interhash = {1832bdc9cc3ea644f28dd10511d0b747},
intrahash = {90346541318e6f510275976872684a3e},
journal = {Biophys. J.},
keywords = {Bilayers; Calcium Calcium; Channel Chemical; Computer Cytosol; Gating; Ion Lipid Models, Receptor Release Ryanodine Simulation;},
month = May,
number = 10,
pages = {3541--3555},
pii = {biophysj.106.099028},
pmid = {17351009},
timestamp = {2009-06-03T11:21:19.000+0200},
title = {{C}a$^{2+}$ stores regulate ryanodine receptor {C}a$^{2+}$ release
channels via luminal and cytosolic {C}a$^{2+}$ sites.},
url = {http://dx.doi.org/10.1529/biophysj.106.099028},
volume = 92,
year = 2007
}