Mechanisms of ryanodine receptor activation

Abstrakt: 

Ryanodine receptor RyR2 is the central protein of cardiac excitation-contraction coupling in adult cardiac myocytes. It is an ion channel responsible for calcium release from the sarcoplasmic reticulum. In physiological state of myocardium the probability of RyR2 opening during the diastole is very low; however, it increases dramatically under pathological conditions. Mutations in RyR2 are the cause of several inherited cardiac arrhythmias. We plan to use molecular dynamics simulations to study the relationship between the structure of different RyR2 domains and the transition between open and closed conformsations of the channel. We also plan to study the relationship between RyR activation/inhibition mechanisms, ultrastructure of calcium release sites, and cellular calcium release, using Markov models and reaction-diffusion modelling.

Odbor: 
biofyzika, molekularna fyziologia
Vedecká časť: 

Stuctural modelling of different mutants and complexes of the RyR2 N-teminal region in vacuo suggested that the activating effect of complexation and of specific mutations may be explained by their effect on the transition energy between the closed and open conformation of RyR2 (Faltinova A, Tomaskova N, Antalik M, Sevcik J, Zahradnikova A. The N-Terminal Region of the Ryanodine Receptor Affects Channel Activation. Front Physiol. 8:443, 2017. doi: 10.3389/fphys.2017.00443. eCollection 2017). In this project we plan to test this hypothesis using molecular dynamics.

Socioekonomický a technologický dopad: 

Publication in prestigiuos journals.

Technická časť: 

NAMD
own software

Prepojenie s grantovými úlohami: 
JRP/2019/836/RyRinHeart (active), APVV-15-0302 (ended), VEGA 2/143/17 (ended)
Spolufinancovanie: 
500.00
Výstupy: 
ZAHRADNÍKOVÁ, Alexandra - MÁJEKOVÁ, Magdaléna - ŠEVČÍK, Jozef. The effect of central helix mutations on the stability of the N-terminal region of the cardiac ryanodine receptor. In 8th Slovak Biophysical Symposium : Book of Contributions. - Košice, Slovakia : Slovak Biophysical Society : COPYVAIT, 2018, p. 42-43. ISBN 978-80-973086-7-4.(APVV-15-0302 : Cytoarchitektúra vápnikovej signalizácie srdcových myocytov vo vývoji hypertrofie myokardu. Vega č. 2/0143/17 : Diastolická funkcia ryanodínového receptora a tvorba arytmogénnych vápnikových vĺn. ITMS 26230120002 : Slovenská infraštruktúra pre vysokovýkonné počítanie – Regionálna konkurencieschopnosť a zamestnanosť. ITMS 26210120002 : Slovenská infraštruktúra pre vysokovýkonné počítanie - Konvergencia. Slovak Biophysical Symposium).