Heterogeneity of Ca2+ gating of skeletal muscle and cardiac ryanodine receptors

The single-channel activity of rabbit skeletal muscle ryanodine receptor (skeletal RyR) and dog cardiac RyR was studied as a function of cytosolic [Ca2+]. The studies reveal that for both skeletal and cardiac RyRs, heterogeneous populations of channels exist, rather than a uniform behavior. Skeletal muscle RyRs displayed two extremes of behavior: 1) low-activity RyRs (LA skeletal RyRs, similar to 35% of the channels) had very low open probability (P-o < 0.1) at all [Ca2+] and remained closed in the presence of Mg2+ (2 mM) and ATP (1 mM); 2) high-activity RyRs (HA skeletal RyRs) had much higher activity and displayed further heterogeneity in their P-o values at low [Ca2+] (<50 nM), and in their patterns of activation by [Ca2+]. Hill coefficients for activation (n(H)(a)) varied from 0.8 to 5.2. Cardiac RyRs, in comparison, behaved more homogeneously. Most cardiac RyRs were closed at 100 nM [Ca2+] and activated in a cooperative manner (n(H)(a) ranged from 1.6 to 5.0), reaching a high P-o (>0.6) in the presence and absence of Mg2+ and ATP. Heart RyRs were much less sensitive (10X) to inhibition by [Ca2+] than skeletal RyRs. The differential heterogeneity of heart versus skeletal muscle RyRs may reflect the modulation required for calcium-induced calcium release versus depolarization-induced Ca2+ release.