Biomaterial Database

Obstruction of ventricular Ca2+ -dependent arrhythmogenicity by inositol 1,4,5-trisphosphate-triggered sarcoplasmic reticulum Ca2+ release. 2018

Joaquim Blanch I Salvador, and Marcel Egger

Department of Physiology, University of Bern, Buehlplatz 5, CH-3012, Bern, Switzerland.

Augmented inositol 1,4,5-trisphosphate (IP3 ) receptor (IP3 R2) expression has been linked to a variety of cardiac pathologies. Although cardiac IP3 R2 function has been in the focus of research for some time, a detailed understanding of its potential role in ventricular myocyte excitation-contraction coupling under pathophysiological conditions remains elusive. The present study focuses on mechanisms of IP3 R2-mediated sarcoplasmic reticulum (SR)-Ca2+ release in ventricular excitation-contraction coupling under IP3 R2-overexpressing conditions by studying intracellular Ca2+ events. We report that, upon IP3 R2 overexpression in ventricular myocytes, IP3 -induced Ca2+ release (IP3 ICR) modulates the SR-Ca2+ content via "eventless" SR-Ca2+ release, affecting the global SR-Ca2+ leak. Thus, IP3 R2 activation could act as a SR-Ca2+ gateway mechanism to escape ominous SR-Ca2+ overload. Our approach unmasks a so far unrecognized mechanism by which "eventless" IP3 ICR plays a protective role against ventricular Ca2+ -dependent arrhythmogenicity. Augmented inositol 1,4,5-trisphosphate (IP3 ) receptor (IP3 R2) function has been linked to a variety of cardiac pathologies including cardiac arrhythmias. The functional role of IP3 -induced Ca2+ release (IP3 ICR) within ventricular excitation-contraction coupling (ECC) remains elusive. As part of pathophysiological cellular remodelling, IP3 R2s are overexpressed and have been repeatedly linked to enhanced Ca2+ -dependent arrhythmogenicity. In this study we test the hypothesis that an opposite scenario might be plausible in which IP3 ICR is part of an ECC protecting mechanism, resulting in a Ca2+ -dependent anti-arrhythmogenic response on the cellular scale. IP3 R2 activation was triggered via endothelin-1 or IP3 -salt application in single ventricular myocytes from a cardiac-specific IP3 R type 2 overexpressing mouse model. Upon IP3 R2 overexpression, IP3 R activation reduced Ca2+ -wave occurrence (46 vs. 21.72%; P < 0.001) while its block increased SR-Ca2+ content (∼29.4% 2-aminoethoxydiphenyl borate, ∼16.4% xestospongin C; P < 0.001), suggesting an active role of IP3 ICR in SR-Ca2+ content regulation and anti-arrhythmogenic function. Pharmacological separation of ryanodine receptor RyR2 and IP3 R2 functions and two-dimensional Ca2+ event analysis failed to identify local IP3 ICR events (Ca2+ puffs). SR-Ca2+ leak measurements revealed that under pathophysiological conditions, "eventless" SR-Ca2+ efflux via enhanced IP3 ICR maintains the SR-Ca2+ content below Ca2+ spark threshold, preventing aberrant SR-Ca2+ release and resulting in a protective mechanism against SR-Ca2+ overload and arrhythmias. Our results support a so far unrecognized modulatory mechanism in ventricular myocytes working in an anti-arrhythmogenic fashion.

UI	MeSH Term	Description	Entries
D002118	Calcium	A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.	Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001145	Arrhythmias, Cardiac	Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction.	Arrhythmia,Arrythmia,Cardiac Arrhythmia,Cardiac Arrhythmias,Cardiac Dysrhythmia,Arrhythmia, Cardiac,Dysrhythmia, Cardiac
D012519	Sarcoplasmic Reticulum	A network of tubules and sacs in the cytoplasm of SKELETAL MUSCLE FIBERS that assist with muscle contraction and relaxation by releasing and storing calcium ions.	Reticulum, Sarcoplasmic,Reticulums, Sarcoplasmic,Sarcoplasmic Reticulums
D015544	Inositol 1,4,5-Trisphosphate	Intracellular messenger formed by the action of phospholipase C on phosphatidylinositol 4,5-bisphosphate, which is one of the phospholipids that make up the cell membrane. Inositol 1,4,5-trisphosphate is released into the cytoplasm where it releases calcium ions from internal stores within the cell's endoplasmic reticulum. These calcium ions stimulate the activity of B kinase or calmodulin.	1,4,5-InsP3,Inositol 1,4,5-Triphosphate,Myo-Inositol 1,4,5-Trisphosphate,1,4,5-IP3,Myoinositol 1,4,5-Triphosphate
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D053496	Inositol 1,4,5-Trisphosphate Receptors	Intracellular receptors that bind to INOSITOL 1,4,5-TRISPHOSPHATE and play an important role in its intracellular signaling. Inositol 1,4,5-trisphosphate receptors are calcium channels that release CALCIUM in response to increased levels of inositol 1,4,5-trisphosphate in the CYTOPLASM.	Inositol 1,4,5-Triphosphate Receptor,Inositol 1,4,5-Triphosphate Receptors,Inositol 1,4,5-Trisphosphate Receptor,1,4,5-INTP Receptor,INSP3 Receptor,INSP3 Receptor Type 1,INSP3 Receptor Type 2,INSP3 Receptor Type 3,IP3 Receptor,Inositol 1,4,5-trisphosphate Receptor Subtype 3,Inositol 1,4,5-trisphosphate Receptor Type 1,Inositol 1,4,5-trisphosphate Receptor Type 2,Inositol 1,4,5-trisphosphate Receptor Type 3,Inositol Triphosphate Receptor,Inositol-1,4,5-Triphosphate Receptor,Receptor, Inositol-1,4,5-triphosphate,Type 1 Inositol 1,4,5-trisphosphate Receptor,Type 3 Inositol 1,4,5-trisphosphate Receptor,Receptor, INSP3,Receptor, IP3,Receptor, Inositol Triphosphate,Triphosphate Receptor, Inositol
D056966	Excitation Contraction Coupling	A process fundamental to muscle physiology whereby an electrical stimulus or action potential triggers a myocyte to depolarize and contract. This mechanical muscle contraction response is regulated by entry of calcium ions into the cell.	Contraction Coupling, Excitation,Contraction Couplings, Excitation,Coupling, Excitation Contraction,Couplings, Excitation Contraction,Excitation Contraction Couplings
D019837	Ryanodine Receptor Calcium Release Channel	A tetrameric calcium release channel in the SARCOPLASMIC RETICULUM membrane of SMOOTH MUSCLE CELLS, acting oppositely to SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES. It is important in skeletal and cardiac excitation-contraction coupling and studied by using RYANODINE. Abnormalities are implicated in CARDIAC ARRHYTHMIAS and MUSCULAR DISEASES.	Calcium-Ryanodine Receptor Complex,RyR1,Ryanodine Receptor 1,Ryanodine Receptor 2,Ryanodine Receptor 3,Ryanodine Receptors,Ca Release Channel-Ryanodine Receptor,Receptor, Ryanodine,RyR2,RyR3,Ryanodine Receptor,Ca Release Channel Ryanodine Receptor,Calcium Ryanodine Receptor Complex,Complex, Calcium-Ryanodine Receptor,Receptor 1, Ryanodine,Receptor 2, Ryanodine,Receptor 3, Ryanodine,Receptor Complex, Calcium-Ryanodine,Receptors, Ryanodine