Ca2+ Stores Regulate Ryanodine Receptor Ca2+ Release Channels via Luminal and Cytosolic Ca2+ Sites Export

@article{citeulike:3388542, abstract = {The free [Ca2+] in endoplasmic/sarcoplasmic reticulum Ca2+ stores regulates excitability of Ca2+ release by stimulating the Ca2+ release channels. Just how the stored Ca2+ regulates activation of these channels is still disputed. One proposal attributes luminal Ca2+-activation to luminal facing regulatory sites, whereas another envisages Ca2+ permeation to cytoplasmic sites. This study develops a unified model for luminal Ca2+ 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 Ca2+ sensors in different parts of the molecule; a luminal activation site (L-site, 60 {micro}M affinity), a cytoplasmic activation site (A-site, 0.9 {micro}M affinity), and a novel cytoplasmic inactivation site (I2-site, 1.2 {micro}M affinity). RyR activation by luminal Ca2+ is demonstrated to occur by a multistep process dubbed luminal-triggered Ca2+ feedthrough. Ca2+ binding to the L-site initiates brief openings (1 ms duration at 1-10 s-1) allowing luminal Ca2+ 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 Ca2+-mediated physiological and pathological processes. 10.1529/biophysj.106.099028}, author = {Laver, Derek R.}, citeulike-article-id = {3388542}, citeulike-linkout-0 = {http://dx.doi.org/10.1529/biophysj.106.099028}, citeulike-linkout-1 = {http://www.biophysj.org/cgi/content/abstract/92/10/3541}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/17351009}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=17351009}, day = {15}, doi = {10.1529/biophysj.106.099028}, journal = {Biophys. J.}, keywords = {cytosol-ca2, luminal-triggered-ca2-feedthrough-hypothesis, ryr-a-site, ryr-l-site, sheep, sr-load, sr-luminal-ca, sr-vesicles}, month = {May}, number = {10}, pages = {3541--3555}, posted-at = {2008-10-09 00:32:49}, priority = {2}, title = {Ca2+ Stores Regulate Ryanodine Receptor Ca2+ Release Channels via Luminal and Cytosolic Ca2+ Sites}, url = {http://dx.doi.org/10.1529/biophysj.106.099028}, volume = {92}, year = {2007} }

TY - JOUR ID - citeulike:3388542 L3 - citeulike-article-id:3388542 N2 - The free [Ca2+] in endoplasmic/sarcoplasmic reticulum Ca2+ stores regulates excitability of Ca2+ release by stimulating the Ca2+ release channels. Just how the stored Ca2+ regulates activation of these channels is still disputed. One proposal attributes luminal Ca2+-activation to luminal facing regulatory sites, whereas another envisages Ca2+ permeation to cytoplasmic sites. This study develops a unified model for luminal Ca2+ 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 Ca2+ sensors in different parts of the molecule; a luminal activation site (L-site, 60 {micro}M affinity), a cytoplasmic activation site (A-site, 0.9 {micro}M affinity), and a novel cytoplasmic inactivation site (I2-site, 1.2 {micro}M affinity). RyR activation by luminal Ca2+ is demonstrated to occur by a multistep process dubbed luminal-triggered Ca2+ feedthrough. Ca2+ binding to the L-site initiates brief openings (1 ms duration at 1-10 s-1) allowing luminal Ca2+ 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 Ca2+-mediated physiological and pathological processes. 10.1529/biophysj.106.099028 IS - 10 JF - Biophys. J. EP - 3555 TI - Ca2+ Stores Regulate Ryanodine Receptor Ca2+ Release Channels via Luminal and Cytosolic Ca2+ Sites VL - 92 SP - 3541 KW - cytosol-ca2 KW - luminal-triggered-ca2-feedthrough-hypothesis KW - ryr-a-site KW - ryr-l-site KW - sheep KW - sr-load KW - sr-luminal-ca KW - sr-vesicles AU - Laver, Derek PY - 2007/05/15/ UR - http://dx.doi.org/10.1529/biophysj.106.099028 ER -