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To determine the critical region of the DHPR responsible for the opening of the RYR, various mutational studies have been conducted. One potential interaction site is the myoplasmic loop between transmembrane domains II and III in the α1 subunit of the DHPR (depicted in Fig.12.10). The voltage-sensing region of the DHPR involved in intramembranous charge movement is believed to reside in the S4 transmembrane segments of the α1 subunit. Pathological disturbances in myoplasmic [Ca++] have been associated with genetic mutations in the RYR or DHPR, or both. Examples of such disturbances include malignant hyperthermia and central core disease, which will be described later. These mutations are typically observed in the myoplasmic portion of the RYR, although mutations have also been observed in the myoplasmic loop in the DHPR. Studies indicate that the protein Stac3 is also crucial for the coupling of the DHPR to the RYR in skeletal muscle. A mutation in Stac3, present in the rare congenital disorder Native American myopathy, results in impaired excitation-contraction coupling in skeletal muscle.

a. Sarcolemma Action potential potential b. Myoplasmic [Ca++] c. Calsequestrin Twitch force Terminal cisternae of SR Actin-myosin interaction DHPR T tubule Ca++ Ca++ SERCA ATP ADP + Pi 0 8040 120 160 200 •Fig. 12.8. Stimulation of a skeletal muscle fiber initiates an action potential in the muscle that travels down the T tubule and induces the release of Ca++ from the terminal cisternae of the sarcoplasmic reticulum (SR). The rise in intracellular [Ca++] causes a contraction. As Ca++ is pumped back into the SR by sarcoplasmic endoplasmic reticulum Ca++-ATPase (SERCA), relaxation occurs. DHPR refers to the dihydropyridine receptor, Pi stands for inorganic phosphate, and RYR stands for ryanodine receptor.

RYR DHPR T tubule cisternae of SR Terminal •Fig. 12.9. An electron micrograph of a triad illustrates the "feet" (arrows) between the T tubule and the sarcoplasmic reticulum (SR), which are believed to be the ryanodine receptors (RYRs) in the SR. Each RYR in the SR is associated with four dihydropyridine receptors (DHPRs) in the T tubule. (From Protasi F, et al. RYR1 and RYR3 have different roles in the assembly of calcium release units of skeletal muscle. Biophys J. 2000;79:2494.)

Relaxation of skeletal muscle occurs as intracellular Ca++ is resequestered by the SR. The uptake of Ca++ into the SR is facilitated by a Ca++ pump called SERCA, which stands for sarcoplasmic endoplasmic reticulum calcium ATPase. This Ca++ pump is not specific to skeletal muscle and can be found in all cells associated with the endoplasmic reticulum. SERCA is the most abundant protein in the SR of skeletal muscle and is distributed throughout the longitudinal tubules and the terminal cisternae. It transports two molecules of Ca++ into its lumen for each molecule of ATP hydrolyzed.

Thus, the twitch contraction Ca++ transient observed (as shown in [figure reference]) is a result of the Ca++ resequestering process during relaxation.

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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