{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:00:45Z","timestamp":1791273645341,"version":"4.1.0"},"reference-count":48,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2004,10]]},"abstract":"<jats:p> Malignant hyperthermia (MH) is an inherited pharmacogenetic disorder caused by mutations in the skeletal muscle ryanodine receptor (RyR1) and the dihydropyridine receptor (DHPR) \u03b1<jats:sub>1S<\/jats:sub>-subunit. We characterized the effects of an MH mutation in the DHPR cytoplasmic III-IV loop of \u03b1<jats:sub>1S<\/jats:sub> (R1086H) on DHPR-RyR1 coupling after reconstitution in dysgenic (\u03b1<jats:sub>1S<\/jats:sub> null) myotubes. Compared with wild-type \u03b1<jats:sub>1S<\/jats:sub>, caffeine-activated Ca<jats:sup>2+<\/jats:sup> release occurred at approximately fivefold lower concentrations in nonexpressing and R1086H-expressing myotubes. Although maximal voltage-gated Ca<jats:sup>2+<\/jats:sup> release was similar in \u03b1<jats:sub>1S<\/jats:sub>- and R1086H-expressing myotubes, the voltage dependence of Ca<jats:sup>2+<\/jats:sup> release was shifted \u223c5 mV to more negative potentials in R1086H-expressing myotubes. Our results demonstrate that \u03b1<jats:sub>1S<\/jats:sub> functions as a negative allosteric modulator of release channel activation by caffeine\/voltage and that the R1086H MH mutation in the intracellular III-IV linker disrupts this negative regulatory influence. Moreover, a low caffeine concentration (2 mM) caused a similar shift in voltage dependence of Ca<jats:sup>2+<\/jats:sup> release in \u03b1<jats:sub>1S<\/jats:sub>- and R1086H-expressing myotubes. Compared with \u03b1<jats:sub>1S<\/jats:sub>-expressing myotubes, maximal L channel conductance ( G<jats:sub>max<\/jats:sub>) was reduced in R1086H-expressing myotubes (\u03b1<jats:sub>1S<\/jats:sub> 130 \u00b1 10.2, R1086H 88 \u00b1 6.8 nS\/nF; P &lt; 0.05). The decrease in G<jats:sub>max<\/jats:sub> did not result from a change in retrograde coupling with RyR1 as maximal conductance-charge movement ratio ( G<jats:sub>max<\/jats:sub>\/Q<jats:sub>max<\/jats:sub>) was similar in \u03b1<jats:sub>1S<\/jats:sub>- and R1086H-expressing myotubes and a similar decrease in G<jats:sub>max<\/jats:sub> was observed for an analogous mutation engineered into the cardiac L channel (R1217H). In addition, both R1086H and R1217H DHPRs targeted normally and colocalized with RyR1 in sarcoplasmic reticulum (SR)-sarcolemmal junctions. These results indicate that the R1086H MH mutation in \u03b1<jats:sub>1S<\/jats:sub> enhances RyR1 sensitivity to activation by both endogenous (voltage sensor) and exogenous (caffeine) activators. <\/jats:p>","DOI":"10.1152\/ajpcell.00173.2004","type":"journal-article","created":{"date-parts":[[2004,6,17]],"date-time":"2004-06-17T00:40:53Z","timestamp":1087432853000},"page":"C1094-C1102","source":"Crossref","is-referenced-by-count":115,"title":["Functional analysis of the R1086H malignant hyperthermia mutation in the DHPR reveals an unexpected influence of the III-IV loop on skeletal muscle EC coupling"],"prefix":"10.1152","volume":"287","author":[{"given":"Regina G.","family":"Weiss","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen M. 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