Role of ryanodine receptor cooperativity in Ca2+‐wave‐mediated triggered activity in cardiomyocytes
Year: 2024
Type: article
Abstract: Ca2+ waves are known to trigger delayed after‐depolarizations that can cause malignant cardiac arrhythmias. However, modelling Ca2+ waves using physiologically realistic models has remained a major challenge. Existing models with low Ca2+ sensitivity of ryanodine receptors (RyRs) necessitate large release currents, leading to an unrealistically large Ca2+ transient amplitude incompatible with the experimental observations. Consequently, current physiologically detailed models of delayed after‐depolarizations resort to unrealistic cell architectures to produce Ca2+ waves with a normal Ca2+ transient amplitude. Here, we address these challenges by incorporating RyR cooperativity into a physiologically detailed model with a realistic cell architecture. We represent RyR cooperativity phenomenologically through a Hill coefficient within the sigmoid function of RyR open probability. Simulations in permeabilized myocytes with high Ca2+ sensitivity reveal that a sufficiently large Hill coefficient is required for Ca2+ wave propagation via the fire–diffuse–fire mechanism. In intact myocytes, propagating Ca2+ waves can occur only within an intermediate Hill coefficient range. Within this range, the spark rate is neither too low, enabling Ca2+ wave propagation, nor too high, allowing for the maintenance of a high sarcoplasmic reticulum load during diastole of the action potential. Moreover, this model successfully replicates other experimentally observed manifestations of Ca2+‐wave‐mediated triggered activity, including phase 2 and phase 3 early after‐depolarizations and high‐frequency voltage–Ca2+ oscillations. These oscillations feature an elevated take‐off potential with depolarization mediated by the L‐type Ca2+ current. The model also sheds light on the roles of luminal gating of RyRs and the mobile buffer ATP in the genesis of these arrhythmogenic phenomena. image Key points Existing mathematical models of Ca2+ waves use an excessively large Ca2+‐release current or unrealistic diffusive coupling between release units. Our physiologically realistic model, using a Hill coefficient in the ryanodine receptor (RyR) gating function to represent RyR cooperativity, addresses these limitations and generates organized Ca2+ waves at Hill coefficients ranging from ∼5 to 10, as opposed to the traditional value of 2. This range of Hill coefficients gives a spark rate neither too low, thereby enabling Ca2+ wave propagation, nor too high, allowing for the maintenance of a high sarcoplasmic reticulum load during the plateau phase of the action potential. Additionally, the model generates Ca2+‐wave‐mediated phase 2 and phase 3 early after‐depolarizations, and coupled membrane voltage with Ca2+ oscillations mediated by the L‐type Ca2+ current. This study suggests that pharmacologically targeting RyR cooperativity could be a promising strategy for treating cardiac arrhythmias linked to Ca2+‐wave‐mediated triggered activity.
Source: The Journal of Physiology
DOI: 10.1113/jp286145
Authors: Mingwang Zhong, Alain Karma
Institution: Northeastern University
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4404566824