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This Article Full Text Full Text (PDF) All Versions of this Article: 288/6/C1222    most recent 00415.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Murayama, T. Articles by Ogawa, Y. Search for Related Content PubMed PubMed Citation Articles by Murayama, T. Articles by Ogawa, Y.

MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

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

¹Department of Pharmacology, Juntendo University School of Medicine, Tokyo; ²Department of Regulatory Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; ³Boston Biomedical Research Institute, Watertown; and ⁴Department of Neurology, Harvard Medical School, Boston, Massachusetts

Submitted 24 August 2004 ; accepted in final form 25 January 2005

Ryanodine receptor (RyR) type 1 (RyR1) exhibits a markedly lower gain of Ca²⁺-induced Ca²⁺ 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 [³H]ryanodine binding, single-channel recordings, and Ca²⁺ release from the SR vesicles. Like CHAPS, domain peptide 4 (DP4, a synthetic peptide corresponding to the Leu²⁴⁴²-Pro²⁴⁷⁷ 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 [³H]ryanodine binding to RyR1 with only minor alterations in the sensitivity to endogenous CICR modulators (Ca²⁺, Mg²⁺, and adenine nucleotide). However, DP4 sensitized RyR1 four- to six-fold to caffeine in the caffeine-induced Ca²⁺ release. Thus the gain of CICR activity critically determines the magnitude and threshold of Ca²⁺ release by drugs such as caffeine. These findings suggest that the low CICR gain of RyR1 is important in normal Ca²⁺ handling in skeletal muscle and that perturbation of this state may result in muscle diseases such as malignant hyperthermia.

malignant hyperthermia; 3-[(3-cholamidopropyl)dimethylammonio]propane sulfonic acid; domain peptide 4

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				A. Chugun, O. Sato, H. Takeshima, and Y. Ogawa Mg2+ activates the ryanodine receptor type 2 (RyR2) at intermediate Ca2+ concentrations Am J Physiol Cell Physiol, January 1, 2007; 292(1): C535 - C544. [Abstract] [Full Text] [PDF]