Ryanodine receptor | EPFL Graph Search

Ryanodine receptors (RyR for short) form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissues and participate in different signaling pathways involving calcium release from intracellular organelles. The RYR2 ryanodine receptor isoform is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells. Etymology The ryanodine receptors are named after the plant alkaloid ryanodine which shows a high affinity to them. Isoforms There are multiple isoforms of ryanodine receptors:

RyR1 is primarily expressed in skeletal muscle
RyR2 is primarily expressed in myocardium (heart muscle)
RyR3 is expressed more widely, but especially in the brain.
Non-mammalian vertebrates typically express two RyR isoforms, referred to as RyR-alpha and RyR-beta.
Many invertebrates, including the model o

Mathematical modeling and numerical simulation of excitation-contraction phenomena in the heart

In this Master thesis we aim at studying some physiological and computational aspects of the excitation-contraction mechanisms in the heart muscle. This phenomenon exhibits many complexities at different spatio-temporal scales. The relevance and applicability of several recent phenomenological and physiologically detailed ionic models will be assessed. The choice of the treated models is based on an equilibrium between results that manage to reproduce correctly the complexity of the cardiac electrophysiology and a weak computational cost in order to solve the large set of ODEs which describe the dynamics of that ionic model. The preferred models include a large part of the more recent electrophysiological discoveries and understandings (e.g. L-type calcium and ryanodine channels) in order to reproduce at best the electrical conduction in the human cardiac tissue based on different experimental or computational measurements. According to these previous remarks, we will perform a thorough testing and quantitative comparison of these models and mechanical activation mechanisms in the framework of the LifeV finite element library. In a second step, a recent model for the description of crossbridge dynamics will be implemented. The importance of using good ionic models makes sense to identify correctly the possible influence on the muscle mechanics activation, which enable the heart to pump blood throughout the entire circulatory system.

2013

Calcium Dynamics and Intercellular Communication in Arterial Smooth Muscle Cells in Vitro

Nadia Halidi

Tissue blood flow is controlled by changes in the diameter of the arteries and arterioles through coordinated contraction and relaxation of smooth muscle cells (SMCs) within the vascular wall. The contraction of SMCs is primarily regulated by the intracellular Ca2+ concentration ([Ca2+]i). An increase in [Ca2+]i, in response to stimuli, can propagate from cell to cell, as an intercellular Ca2+ wave along the vessel wall and can activate the process of contraction. The aim of this thesis is to elucidate the mechanisms underlying intercellular Ca2+ wave propagation between SMCs. In the first part of this thesis, we used A7r5 cells, a rat aortic SMC line, loaded with the fluorescent Ca2+ dye Fluo-4 to study intercellular Ca2+ wave propagation. Local mechanical stimulation evoked a Ca2+ wave in the stimulated cell that failed to propagate to neighboring cells. Using primary cultured rat mesenteric smooth muscle cells (pSMCs) instead, intercellular Ca2+ wave propagation was observed. To understand the difference in junctional communication between A7r5 and pSMCs, we investigated the expression of connexin37 (Cx37), Cx40, Cx43 and Cx45. RNA and protein analysis demonstrated that Cx40 – in contrast to A7r5 cells – is not expressed in pSMCs. To confirm that coexpression of Cx40 and Cx43 interfered with junctional communication, we used 6B5N cells, a clone of A7r5 cells with a higher Cx43:Cx40 expression ratio. Junctional communication, assessed by transfer of Lucifer Yellow and propagation of Ca2+ waves, was comparable between 6B5N cells and pSMCs. In addition, Ca2+ wave propagation was inhibited with the connexin-mimetic peptide 43Gap 26, that targets Cx43. Our results demonstrate that Cx43 gap junctions are primarily involved in mediating intercellular Ca2+ waves between pSMCs, and the coexpression of Cx43 with Cx40 may interfere with Cx43 gap junction formation, affecting cell-cell communication. In the second part of this thesis, we applied the microcontact printing technique to culture pSMCs on collagen lines. The aligned arrangement of the cells facilitates the observation of Ca2+ wave progression from one cell to another. To induce a Ca2+ wave, a single pSMC was locally stimulated with a micropipette (transientmechanical stimulation) or by microejection of KCl. Mechanical stimulation evoked two distinct Ca2+ waves: 1) a fast wave (∼2 mm/s) that propagated to all observed neighbouring cells, and 2) a slow wave (∼20 µm/s), that was most often limited in propagation to the first cell. KCl induced only fast Ca2+ waves of the same velocity as the mechanically-induced fast waves. Inhibition of gap junctions, voltage-operated calcium channels, inositol 1,4,5-trisphosphate (IP3) and ryanodine receptors, showed that the fast wave was due to gap junction mediated membrane depolarization and subsequent Ca2+ influx, whereas, the slow wave was due to Ca2+ release primarily through IP3 receptors. Together, these results suggest a mechanism by which intercellular Ca2+ waves can propagate between SMCs of the arterial wall.

EPFL2011

Propagation of fast and slow intercellular Ca2+ waves in primary cultured arterial smooth muscle cells

Jean-Louis Bény, Nadia Halidi, Jean-Jacques Meister

Smooth muscle contraction is regulated by changes in cytosolic Ca2+ concentration (Ca2+). In response to stimulation, Ca2+ increase in a single cell can propagate to neighbouring cells through gap junctions, as intercellular Ca2+ waves. To investigate the mechanisms underlying Ca2+ wave propagation between smooth muscle cells, we used primary cultured rat mesenteric smooth muscle cells (pSMCs). Cells were aligned with the microcontact printing technique and a single pSMC was locally stimulated by mechanical stimulation or by microejection of KCl. Mechanical stimulation evoked two distinct Ca2+ waves: (1) a fast wave (2 mm/s) that propagated to all neighbouring cells, and (2) a slow wave (20 mu m/s) that was spatially limited in propagation. KCl induced only fast Ca2+ waves of the same velocity as the mechanically induced fast waves. Inhibition of gap junctions, voltage-operated calcium channels, inositol 1,4,5-trisphosphate (IP3) and ryanodine receptors, shows that the fast wave was due to gap junction mediated membrane depolarization and subsequent Ca2+ influx through voltage-operated Ca2+ channels, whereas, the slow wave was due to Ca2+ release primarily through IP3 receptors. Altogether, these results indicate that temporally and spatially distinct mechanisms allow intercellular communication between SMCs. In intact arteries this may allow fine tuning of vessel tone. (C) 2011 Elsevier Ltd. All rights reserved.

2011

Calcium Dynamics and Intercellular Communication in Arterial Smooth Muscle Cells in Vitro

Nadia Halidi

EPFL2011