{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T19:46:13Z","timestamp":1762112773709},"reference-count":40,"publisher":"Rockefeller University Press","issue":"1","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,1,1]]},"abstract":"<jats:p>DP4 is a 36-residue synthetic peptide that corresponds to the Leu2442-Pro2477 region of RyR1 that contains the reported malignant hyperthermia (MH) mutation site. It has been proposed that DP4 disrupts the normal interdomain interactions that stabilize the closed state of the Ca2+ release channel (Yamamoto, T., R. El-Hayek, and N. Ikemoto. 2000. J. Biol. Chem. 275:11618\u201311625). We have investigated the effects of DP4 on local SR Ca2+ release events (Ca2+ sparks) in saponin-permeabilized frog skeletal muscle fibers using laser scanning confocal microscopy (line-scan mode, 2 ms\/line), as well as the effects of DP4 on frog SR vesicles and frog single RyR Ca2+ release channels reconstituted in planar lipid bilayers. DP4 caused a significant increase in Ca2+ spark frequency in muscle fibers. However, the mean values of the amplitude, rise time, spatial half width, and temporal half duration of the Ca2+ sparks, as well as the distribution of these parameters, remained essentially unchanged in the presence of DP4. Thus, DP4 increased the opening rate, but not the open time of the RyR Ca2+ release channel(s) generating the sparks. DP4 also increased [3H]ryanodine binding to SR vesicles isolated from frog and mammalian skeletal muscle, and increased the open probability of frog RyR Ca2+ release channels reconstituted in bilayers, without changing the amplitude of the current through those channels. However, unlike in Ca2+ spark experiments, DP4 produced a pronounced increase in the open time of channels in bilayers. The same peptide with an Arg17 to Cys17 replacement (DP4mut), which corresponds to the Arg2458-to-Cys2458 mutation in MH, did not produce a significant effect on RyR activation in muscle fibers, bilayers, or SR vesicles. Mg2+ dependence experiments conducted with permeabilized muscle fibers indicate that DP4 preferentially binds to partially Mg2+-free RyR(s), thus promoting channel opening and production of Ca2+ sparks.<\/jats:p>","DOI":"10.1085\/jgp.119.1.15","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:50:20Z","timestamp":1027702220000},"page":"15-32","update-policy":"http:\/\/dx.doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["Interdomain Interactions within Ryanodine Receptors Regulate Ca2+ Spark Frequency in Skeletal Muscle"],"prefix":"10.1085","volume":"119","author":[{"given":"Alexander","family":"Shtifman","sequence":"first","affiliation":[{"name":"aUniversity of Maryland School of Medicine, Department of Biochemistry and Molecular Biology, Baltimore, MD 21201"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher W.","family":"Ward","sequence":"additional","affiliation":[{"name":"aUniversity of Maryland School of Medicine, Department of Biochemistry and Molecular Biology, Baltimore, MD 21201"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"bBoston Biomedical Research Institute, Department of Muscle Research, Watertown, MA 02472"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianli","family":"Wang","sequence":"additional","affiliation":[{"name":"cUniversity of Wisconsin School of Medicine, Department of Physiology, Madison, WI 53706"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beth","family":"Olbinski","sequence":"additional","affiliation":[{"name":"cUniversity of Wisconsin School of Medicine, Department of Physiology, Madison, WI 53706"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hector H.","family":"Valdivia","sequence":"additional","affiliation":[{"name":"cUniversity of Wisconsin School of Medicine, Department of Physiology, Madison, WI 53706"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriaki","family":"Ikemoto","sequence":"additional","affiliation":[{"name":"bBoston Biomedical Research Institute, Department of Muscle Research, Watertown, MA 02472"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin F.","family":"Schneider","sequence":"additional","affiliation":[{"name":"aUniversity of Maryland School of Medicine, Department of Biochemistry and Molecular Biology, Baltimore, MD 21201"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2001,12,17]]},"reference":[{"key":"2023072616550410600_Balogetal2001","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1016\/S0006-3495(01)75854-7","article-title":"Divergent effects of the malignant hyperthermia-susceptible arg(615)\u2192cys mutation on the Ca2+ and Mg2+ dependence of the RyR1","volume":"81","author":"Balog","year":"2001","journal-title":"Biophys. 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