Postulated role of interdomain interactions within the type 1 ryanodine receptor in the low gain of Ca²⁺-induced Ca²⁺ release activity of mammalian skeletal muscle sarcoplasmic reticulum

Abstract

Ryanodine receptor (RyR) type 1 (RyR1) exhibits a markedly lower gain of Ca(2+)-induced Ca(2+) release (CICR) activity than RyR type 3 (RyR3) in the sarcoplasmic reticulum (SR) of mammalian skeletal muscle (selective stabilization of the RyR1 channel), and this reduction in the gain is largely eliminated using 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS). We have investigated whether the hypothesized interdomain interactions within RyR1 are involved in the selective stabilization of the channel using [(3)H]ryanodine binding, single-channel recordings, and Ca(2+) release from the SR vesicles. Like CHAPS, domain peptide 4 (DP4, a synthetic peptide corresponding to the Leu(2442)-Pro(2477) region of RyR1), which seems to destabilize the interdomain interactions, markedly stimulated RyR1 but not RyR3. Their activating effects were saturable and nonadditive. Dantrolene, a potent inhibitor of RyR1 used to treat malignant hyperthermia, reversed the effects of DP4 or CHAPS in an identical manner. These findings indicate that RyR1 is activated by DP4 and CHAPS through a common mechanism that is probably mediated by the interdomain interactions. DP4 greatly increased [(3)H]ryanodine binding to RyR1 with only minor alterations in the sensitivity to endogenous CICR modulators (Ca(2+), Mg(2+), and adenine nucleotide). However, DP4 sensitized RyR1 four- to six-fold to caffeine in the caffeine-induced Ca(2+) release. Thus the gain of CICR activity critically determines the magnitude and threshold of Ca(2+) release by drugs such as caffeine. These findings suggest that the low CICR gain of RyR1 is important in normal Ca(2+) handling in skeletal muscle and that perturbation of this state may result in muscle diseases such as malignant hyperthermia.

Calcium-Induced Calcium Release in Skeletal Muscle

“…It seems likely that Ca 2ϩ sparks in intact fibers require RyR3 channels as Pouvreau et al (217) have shown. Although CICR does not appear to be involved in the production of Ca 2ϩ sparks as discussed above, the RyR3 requirement is reminiscent of the findings of Ogawa and colleagues that CICR in RyR1 or RyR␣, but not RyR3 or RyR␤, is somehow "stabilized" in the physiological state (185,188,189).…”

“…Murayama and Ogawa (189) have reported that bovine RyR1 is also "stabilized" in the physiological state but RyR3 is not, as in amphibian RyRs. Murayama et al (185,189) have suggested that a change in the interdomain interaction due to CHAPS treatment is the main factor for the "destabilization," but in the case of RyR1 (not RyR␣), the removal of FKBP12 also contributes. These findings suggest that RyR1 in the low-activity group is in a more physiological condition.…”

Mg2+activates the ryanodine receptor type 2 (RyR2) at intermediate Ca2+concentrations

“…In the SR membrane of skeletal muscles, on the other hand, the activity of RyR1 is selectively suppressed to about oneseventh over the whole range of Ca 2ϩ concentrations compared with RyR3, as evidenced by a reduced affinity for [ 3 H]ryanodine to a comparable extent without a change in Ca 2ϩ dependence (22,24,30). This means that the attenuating coefficient (1/7-1/8) for RyR1 is constant over the whole range of Ca 2ϩ concentrations, without a change in the affinities for the divalent cations of the A-or I-site.…”

“…In the presence of Mg 2ϩ , it was more remarkable. Whereas the stimulatory effect of 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), which was used to remove the selective suppression of RyR1, was maximum at 2% on mammalian skeletal muscles (22), the maximum effect was obtained at 0.1%-0.2% with rat ventricular SR. CHAPS at 1% was rather inhibitory to rat or rabbit RyR2 (data not shown). It should be pointed out that the stimulatory effect of CHAPS was also dependent on the presence of Mg 2ϩ .…”

“…A reduction in the affinity for the ligand, [ 3 H]ryanodine, accompanied this suppression (24). The interdomain interaction between region 1 (the NH 2 -terminal domain) and region 2 (the central domain) of RyR1 was found to be the main mechanism underlying the suppression (22). This interdomain interaction has also attracted the keen interest of investigators in view of its probable role in malignant hyperthermia (10).…”