Ryanodine receptors as pharmacological targets for heart disease

Abstract

Calcium release from intracellular stores plays an important role in the regulation of muscle contraction and electrical signals that determine the heart rhythm. The ryanodine receptor (RyR) is the major calcium (Ca 2+ ) release channel required for excitation-contraction coupling in the heart. Recent studies have demonstrated that RyR are macromolecular complexes comprising of 4 pore-forming channel subunits, each of which is associated with regulatory subunits. Clinical and experimental studies over the past 5 years have provided compelling evidence that intracellular Ca 2+ release channels play a pivotal role in the development of cardiac arrhythmias and heart failure. Changes in the channel regulation and subunit composition are believed to cause diastolic calcium leakage from the sarcoplasmic reticulum, which could trigger arrhythmias and weaken cardiac contractility. Therefore, cardiac RyR have emerged as potential therapeutic targets for the treatment of heart disease. Consequently, there is a strong desire to identify and/or develop novel pharmacological agents that may target these Ca 2+ signaling pathways. Pharmacological agents known to modulate RyR in the heart, and their potential application towards the treatment of heart disease are discussed in this review.

Role of abnormal sarcoplasmic reticulum function in atrial fibrillation

“…Excitation-contraction coupling (ECC) is the fundamental process by which an action potential initiates contraction of a cardiomyocyte [5]. Plasma membrane depolarization leads to the influx of Ca 2+ via voltage-gated L-type Ca 2+ channels, which in turn triggers a much greater release of Ca 2+ from the SR via ryanodine receptor type 2 (RyR2) channels ( Figure 1).…”

Design, Synthesis and Biological Activities of Novel Trifluoromethylated Phthalic Acid Diamides Derivatives

“…其中 具有代表性的有: 氟虫酰胺(Flubenidamide, A)、氯虫酰 胺(Rynaxypyr, B)和氰虫酰胺(Cyazypyr, C, Scheme 1). 这两类化合物的作用机理是激活昆虫体内的钙离子通 道--鱼尼丁受体, 引起钙离子的持续释放, 从而导致 昆虫死亡 [8,9] .…”

Targeting ryanodine receptors for anti-arrhythmic therapy

“…Because RyR2 also plays an important role during excitation-contraction coupling, it is important that antiarrhythmic compounds targeting the RyR2 channel complex will not interfere with systolic SR Ca 2+ release. At the same time, inhibition of diastolic SR Ca 2+ release is a desirable feature of compounds that could prevent arrhythmias [22] . RyR2 activity can be modulated by numerous natural and pharmacological compounds, as reviewed elsewhere in more detail [22][23][24] .…”

“…At the same time, inhibition of diastolic SR Ca 2+ release is a desirable feature of compounds that could prevent arrhythmias [22] . RyR2 activity can be modulated by numerous natural and pharmacological compounds, as reviewed elsewhere in more detail [22][23][24] . These compounds may modulate RyR2 in various ways, including by modulating channel gating, ion channel translocation, RyR2 subunit composition, or posttranslational modifi cations.…”

“…Given that there are many excellent reviews on strategies to modify intracellular signaling to reduce RyR2 activation [21,22] , we will restrict the scope of this review mainly to pharmacological strategies to stabilize RyR2 directly to reduce arrhythmic potential. Because RyR2 also plays an important role during excitation-contraction coupling, it is important that antiarrhythmic compounds targeting the RyR2 channel complex will not interfere with systolic SR Ca 2+ release.…”