The dihydropyridine receptor (DHPR), an L-type voltage-gated Ca++ channel, is believed to interact with the ryanodine receptor (RYR) at the T tubule membrane. The DHPR consists of five subunits, one of which binds dihydropyridine channel-blocking drugs and plays a crucial role in inducing the release of Ca++ from the sarcoplasmic reticulum (SR) when the action potential passes down the T tubule. Interestingly, Ca++ influx through the DHPR is not necessary for initiating Ca++ release from the SR. Skeletal muscle is capable of contracting even in the absence of extracellular Ca++ or with a mutated DHPR that cannot conduct Ca++. Instead, it is believed that a conformational change in the DHPR, triggered by the action potential passing down the T tubule, leads to the opening of the RYR and subsequent release of Ca++ into the myoplasm.

Structural analysis, including freeze-fracture techniques, has provided evidence suggesting a close physical association between the DHPR and RYR. The DHPR in the T tubule membrane appears to be located directly opposite the four corners of the underlying homotetrameric RYR channel in the SR membrane. Further studies have shown that the coupling of the DHPR and RYR during excitation-contraction coupling in skeletal muscle SR relies on the critical protein Stac3, specifically the SH3-cysteine rich domain 3 protein. Notably, Stac3 is absent in cardiac muscle, which relies on Ca++ influx through the sarcolemma instead of direct coupling between the DHPR and RYR.

Other proteins found near the RYR include calsequestrin, triadin, and junctin. Calsequestrin, located in the lumen of the terminal cisternae, is a low-affinity Ca++-binding protein. It plays a crucial role in establishing a favorable concentration gradient that facilitates the efflux of Ca++ from the SR into the myoplasm when the RYR opens. Triadin and junctin, present in the terminal cisternae membrane, bind both RYR and calsequestrin. Their presence helps anchor calsequestrin near the RYR, increasing the buffering capacity of Ca++ at the site of Ca++ release. Additionally, the histidine-rich calcium-binding protein, another low-affinity Ca++-binding protein in the SR lumen, has been identified. Although less abundant than calsequestrin, it is believed to bind to triadin in a Ca++-dependent manner, suggesting a potential role beyond serving as a Ca++ buffer. Furthermore, there is evidence indicating the presence of store-operated Ca entry (SOCE) in skeletal muscle, particularly via the Orai/Stim1 complex, during tetany. While inhibition of Ca++ influx does not impact excitation-contraction coupling, it does reduce maximal tetanic tension at high rates of electrical stimulation, suggesting the possibility of intracellular Ca++ extrusion during tetany, compensated by Ca++ influx to maintain maximal tetanic tension.
At the T tubule membrane, the RYR is thought to interact with a protein called the dihydropyridine receptor (DHPR). DHPR is an L-type voltage-gated Ca++ channel with five subunits. One of these subunits binds the dihydropyridine class of channel-blocking drugs and appears to be crucial for the ability of the action potential in the T tubule to induce release of Ca++ from the SR. However, influx of Ca++ into the cell through the DHPR is not needed for the initiation of Ca++ release from the SR. In fact, skeletal muscle is able to contract in the absence of extracellular Ca++ or with a mutated DHPR that does not conduct Ca++ . Instead, release of Ca++ from the terminal cisternae of the SR is thought to result from a conformational change in the DHPR as the action potential passes down the T tubule, and this conformational change in the DHPR, by means of a protein-protein interaction, opens the RYR and releases Ca++ into the myoplasm.
Structural analysis, including the use of freeze-fracture techniques, provides evidence for a close physical association of DHPR and RYR (see
Fig. 12.9 ). DHPR in the T tubule membrane appears to reside directly opposite the four corners of the underlying homotetrameric RYR channel in the SR membrane. Studies have shown that the SH3-cysteine rich domain 3 protein Stac3 is also critical for coupling of the DHPR to the RYR during excitation-contraction coupling in skeletal muscle SR. Stac3 is not present in cardiac muscle, which relies on Ca++ influx through the sarcolemma to initiate Ca++ release from the RYR instead of the direct coupling of the DHPR and the RYR in skeletal muscle.
Other proteins that reside near the RYR include calsequestrin, triadin, and junctin (see
Fig. 12.10 ). Calsequestrin is a low-affinity Ca++-binding protein that is present in the lumen of the terminal cisternae. It allows Ca++ to be “stored” at high concentration and thereby establishes a favorable concentration gradient that facilitates the efflux of Ca++ from the SR into the myoplasm when the RYR opens. Triadin and junctin are in the terminal cisternae membrane and bind both RYR and calsequestrin; they could anchor calsequestrin near the RYR and thereby increase Ca++ buffering capacity at the site of Ca++ release. Histidine-rich calcium-binding protein is another low-affinity Ca++-binding protein in the SR lumen, although it is less abundant than calsequestrin. It appears to bind triadin in a Ca++-dependent manner, which raises the possibility that it has a role more important than serving simply as a Ca++ buffer. There is also evidence for the presence of store-operated Ca entry (SOCE) in skeletal muscle (e.g., via the Orai/Stim1 complex) during tetany. Inhibition of Ca influx did not affect excitation-contraction coupling but did reduce maximal tetanic tension at high rates of electrical stimulation, which suggests that there may be some extrusion of intracellular Ca during tetany, which is compensated by Ca influx to maintain maximal tetanic tension.
•Fig. 12.7. Skeletal Muscle Is Voluntary Muscle Controlled by the Central Nervous System, With Efferent Signals (i.e., action potentials) Passing Through an α Motor Neuron to Muscle Fibers. Eachmotorneuronmayinnervatemanymusclefiberswithinamuscle,althougheachmusclefiberisinnervatedbyonlyonemotorneuron(A). Ascanningelectronmicrograph(B) showsinnervationofseveralmusclefibersbyasinglemotorneuron.(B, FromBloomW,FawcettDW:A Textbook of Physiology. 12thed.NewYork:Chapman&Hall;1994.)