The luminal Ca2+ regulation of cardiac ryanodine receptor (RyR2) was explored at the single channel level. The luminal Ca2+ and Mg2+ sensitivity of single CSQ2-stripped and CSQ2-associated RyR2 channels was defined. Action of wild-type CSQ2 and of two mutant CSQ2s (R33Q and L167H) was also compared. Two luminal Ca2+ regulatory mechanism(s) were identified. One is a RyR2-resident mechanism that is CSQ2 independent and does not distinguish between luminal Ca2+ and Mg2+. This mechanism modulates the maximal efficacy of cytosolic Ca2+ activation. The second luminal Ca2+ regulatory mechanism is CSQ2 dependent and distinguishes between luminal Ca2+ and Mg2+. It does not depend on CSQ2 oligomerization or CSQ2 monomer Ca2+ binding affinity. The key Ca2+-sensitive step in this mechanism may be the Ca2+-dependent CSQ2 interaction with triadin. The CSQ2-dependent mechanism alters the cytosolic Ca2+ sensitivity of the channel. The R33Q CSQ2 mutant can participate in luminal RyR2 Ca2+ regulation but less effectively than wild-type (WT) CSQ2. CSQ2-L167H does not participate in luminal RyR2 Ca2+ regulation. The disparate actions of these two catecholaminergic polymorphic ventricular tachycardia (CPVT)-linked mutants implies that either alteration or elimination of CSQ2-dependent luminal RyR2 regulation can generate the CPVT phenotype. We propose that the RyR2-resident, CSQ2-independent luminal Ca2+ mechanism may assure that all channels respond robustly to large (>5 muM) local cytosolic Ca2+ stimuli, whereas the CSQ2-dependent mechanism may help close RyR2 channels after luminal Ca2+ falls below approximately 0.5 mM.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2279168 | PMC |
http://dx.doi.org/10.1085/jgp.200709907 | DOI Listing |
Sci Rep
November 2024
TSUMURA Kampo Research Laboratories, Research & Development Division, TSUMURA & CO., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, 300-1192, Japan.
Biomedicines
October 2024
Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile.
: Breast cancer, a global health challenge, significantly impacts women worldwide, causing morbidity, disability, and mortality. To analyze the role of genes encoding S100 calcium-binding proteins and their relationship with radiation as possible markers in breast carcinogenesis. The normal MCF-10F cell line was used to study the role of ionizing radiation and estrogen to induce distinct stages of malignancy giving rise to an in vitro experimental breast cancer model.
View Article and Find Full Text PDFJ Physiol
December 2024
Physics Department and Center for Interdisciplinary Research in Complex Systems, Northeastern University, Boston, MA, USA.
Ca waves are known to trigger delayed after-depolarizations that can cause malignant cardiac arrhythmias. However, modelling Ca waves using physiologically realistic models has remained a major challenge. Existing models with low Ca sensitivity of ryanodine receptors (RyRs) necessitate large release currents, leading to an unrealistically large Ca transient amplitude incompatible with the experimental observations.
View Article and Find Full Text PDFSci Adv
November 2024
Institute of Plant Biochemistry and Photosynthesis, Consejo Superior de Investigaciones Cientificas and University of Seville, Seville 41092, Spain.
Shifts in cytosolic pH have been recognized as key signaling events and mounting evidence supports the interdependence between H and Ca signaling in eukaryotic cells. Among the cellular pH-stats, K/H exchange at various membranes is paramount in plant cells. Vacuolar K/H exchangers of the NHX (Na,K/H exchanger) family control luminal pH and, together with K and H transporters at the plasma membrane, have been suggested to also regulate cytoplasmic pH.
View Article and Find Full Text PDFJ Mol Cell Cardiol
December 2024
Institute for Experimental Cardiovascular Medicine, University Heart Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany; Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany. Electronic address:
Background: Efficient excitation-contraction coupling of mammalian ventricular cardiomyocytes depends on the transverse-axial tubular system (TATS), a network of surface membrane invaginations. TATS enables tight coupling of sarcolemmal and sarcoplasmic reticulum membranes, which is essential for rapid Ca-induced Ca release, and uniform contraction upon electrical stimulation. The majority of TATS in healthy ventricular cardiomyocytes is composed of transverse tubules (TT, ∼90 % of TATS in rabbit).
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!