AvarietyofmutationalstudieshavebeenconductedtoascertaintheregionoftheDHPRthatiscriticalforopeningoftheRYR.Onepossiblesiteofinteraction(depictedin
Fig.12.10 )isthemyoplasmicloopbetweentransmembranedomainsIIandIIIintheα1subunitoftheDHPR.Thevoltage-sensingregionoftheDHPRinvolvedinintramembranouschargemovementisthoughttoresideintheS4transmembranesegmentsoftheα1subunit.GeneticmutationsintheRYRorDHPR,orinboth,havebeenassociatedwithpathologicaldisturbancesinmyoplasmic[Ca++].Suchdisturbancesincludemalignanthyperthermiaandcentralcoredisease,asdescribedlater.ThesemutationsaretypicallyobservedinthemyoplasmicportionoftheRYR,althoughmutationshavealsobeenobservedinamyoplasmicloopintheDHPR.ResultsofstudiesindicatethattheproteinStac3isalsoimportantforthecouplingoftheDHPRtotheRYRinskeletalmuscleandthatamutationinStac3thatispresentintherarecongenitaldisorderNativeAmericanmyopathyresultsinimpairedexcitation-contractioncouplinginskeletalmuscle.
a. Action potential potential Sarcolemma b. Myoplasmic [Ca++] c. Twitch force Calsequestrin Terminal cisternae of SRRYR Actin-myosin interaction DHPR T tubule Ca++ Ca++ SERCA ATP ADP + Pi 0 8040 120 160 200 •Fig. 12.8. A, StimulationofaskeletalmusclefiberinitiatesanactionpotentialinthemusclethattravelsdowntheTtubuleandinducesreleaseofCa++ fromtheterminalcisternaeofthesarcoplasmicreticulum(SR).Theriseinintracellular[Ca++]causesacontraction.AsCa++ ispumpedbackintotheSRbysarcoplasmicendoplasmicreticulumCa++-ATPase(SERCA),relaxationoccurs.DHPR,dihydropyridinereceptor;Pi,inorganicphosphate;RYR,ryanodinereceptor.B, Timecoursesoftheactionpotential,myoplasmicCa++ transient,andforceofthetwitchcontraction.
Terminal T tubule RYR DHPR cisternae of SR •Fig. 12.9. A, Electronmicrographofatriadillustratingthe“feet”(arrows) betweentheTtubuleandthesarcoplasmicreticulum(SR),whicharethoughttobetheryanodinereceptors(RYRs)intheSR.B, EachRYRintheSRisassociatedwithfourdihydropyridinereceptors(DHPRs)intheTtubule.(FromProtasiF,etal.RYR1andRYR3havedifferentrolesintheassemblyofcalciumreleaseunitsofskeletalmuscle.Biophys J. 2000;79:2494.)
Relaxation of skeletal muscle occurs as intracellular Ca++ is resequestered by the SR. Uptake of Ca++ into the SR is due to the action of a Ca++ pump (i.e., Ca++-ATPase). This pump is not unique to skeletal muscle; it is found in all cells in association with the endoplasmic reticulum. Accordingly, it is named SERCA, which stands for sarcoplasmic endoplasmic reticulum calcium ATPase. SERCA is the most abundant protein in the SR of skeletal muscle, and it is distributed throughout the longitudinal tubules and the terminal cisternae as well. It transports two molecules of Ca++ into its lumen for each molecule of ATP hydrolyzed.
Thus the Ca++ transient seen during a twitch contraction (see