Effect of calmodulin on Ca2+-induced Ca2+ release of skeletal muscle from mutant mice expressing either ryanodine receptor type 1 or type 3

 We analyzed the effects of calmodulin (CaM) on Ca²⁺-induced Ca²⁺ release (CICR) in mouse skeletal muscle cells expressing only ryanodine receptor type 1 (RyR-1) or type 3 (RyR-3) following targeted disruption of one of the RyR genes. Under Mg²⁺-free conditions, CaM potentiated CICR via RyR-3 at low Ca²⁺ concentrations (pCa≥6) but inhibited CICR at high Ca²⁺ concentrations (pCa≤5). On the other hand, CaM potentiated CICR via RyR-1 between pCa 7 and pCa 5. Greater concentrations of CaM were required for potentiation of CICR at pCa 6 than for the inhibition at pCa 5 in the RyR-3-expressing cells. Similarly, higher concentrations of CaM were required for the potentiation of CICR via RyR-1 at pCa 6 than potentiation at pCa 5. In the presence of Mg²⁺ and β,γ-methyleneadenosine 5′-trisphosphate (AMPOPCP), the same differential effects of CaM on the CICR via the different subtypes of RyR were observed. These data suggest that multiple CaM-binding sites are involved in the differential effects on RyR-1 and RyR-3. These effects of CaM are important for the evaluation of the physiological roles of RyRs. Received: 5 May 1998 / Received after revision: 14 August 1998 / Accepted: 3 September 1998