Proteins within the intracellular calcium store determine cardiac RyR channel activity and cardiac output

The contractile function of the heart requires the release of Ca²⁺ from intracellular Ca²⁺ stores in the sarcoplasmic reticulum (SR) of cardiac muscle cells. The efficacy of Ca²⁺ release depends on the amount of Ca²⁺ loaded into the Ca²⁺ store and the way in which this 'Ca²⁺ load' influences the activity of the cardiac ryanodine receptor Ca²⁺ release channel (RyR2). The effects of the Ca²⁺ load on Ca²⁺ release through RyR2 are facilitated by: (i) the sensitivity of RyR2 itself to luminal Ca²⁺ concentrations; and (ii) interactions between the cardiac Ca²⁺-binding protein calsequestrin (CSQ) 2 and RyR2, transmitted through the 'anchoring' proteins junctin and/or triadin. Mutations in RyR2 are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT) and sudden cardiac death. The tachycardia is associated with changes in the sensitivity of RyR2 to luminal Ca²⁺. Triadin-, junctin- or CSQ-null animals survive, but their longevity and ability to tolerate stress is compromised. These studies reveal the importance of the proteins in normal muscle function, but do not reveal the molecular nature of their functional interactions, which must be defined before changes in the proteins leading to CPVT and heart disease can be understood. Herein, we discuss known interactions between the RyR, triadin, junctin and CSQ with emphasis on the cardiac isoforms of the proteins. Where there is little known about the cardiac isoforms, we discuss evidence from skeletal isoforms.