Excitationcontraction Coupling System

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ECC is accomplished by the sarcotubular system, an arrangement of specialized sarcolemmal and intracellular membranes that functions to control and amplify the ability of the AP to switch the activity of the contractile system on and off. It does so by creating electrochemical signals between the sarcolemma and intracellular organelles; these signals occur much more rapidly than would be possible by simple diffusion of the signaling molecule (in this case, Ca ions).

The sarcotubular system consists of two main components, transverse or T-tubules and the sacroplasmic reticulum (SR)7-12-13 (see G-hH; Fig. 3-3). T-tubules are transverse invaginations of the sarcolemma that are concentrated at the Z line of the sarcomere (see below). The SR is a longitudinally oriented system of intracellular membranous sacs and tubules consisting of collar-like structures encircling the contractile filaments at 1- to 2-Mm spacings and forming repeating closed compartments that extend along the length of each myofibril from cross striation to cross striation. At the end of each collar is a bulge (cistern) that closely abuts a T-tubule, creating a dyad or sometimes a triad structure. The gap between the cistern and nearby T-tubule is bridged by structures called feet.

The SR contains a large store of Ca ions that are released into the cytoplasm as a result of a process termed Ca-induced Ca release (CICR)7-8-14-21 that takes place within or near the dyad. At any point in time, the bulk of Ca ions within the SR is associated with binding proteins, for example, calsequestrin. The details of CICR have been illuminated by Ca "spark" studies employing Ca concentration-sensitive bioluminescent intracellular dyes in conjunction with confocal microscopy17-21 (Fig. 3-5). As indicated earlier, DHP receptor Ca channels are concentrated in the T-tubule region forming the dyad. The adjacent SR membranes in the dyad contain Ca release channels (RyRs)7'8'16'25 that bridge the cisternal membrane near the foot proteins of the dyad. When the AP depolarizes the cell membrane in the dyad region, the voltage-sensitive DHP receptor channel gate opens, allowing movement of Ca from the extracellular space across the sarcolemma into the gap region of the dyad. Nearby RyR channels are activated (opened) by the local rise in Ca concentration in the dyad,725 resulting in very rapid release of much larger amounts of Ca ions from the SR cisternae into the cytoplasm (causing the intracellular Ca "spike" or transient26 detectable with bioluminescent dyes) (Fig. 3-6). This large amount of Ca ions in turn activates the contractile system (see below).

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Excitation Contraction Coupling Steps

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Figure 3-5: Schematic of Ca-induced Ca release from SR resulting in a Ca "spark." Opening of sarcolemmal (SL) L-type Ca channel results in movement of a relatively small amount of Ca ions into the cell. The latter causes opening of a number of nearby RyR channels (Ca release unit) with local release of a large amount of Ca ions from the SR and appearance of a "spark," as bioluminescent dye responds to change in local Ca concentration. (From Williams.8 Reproduced with permission of the publisher.)

Excitation Contraction Coupling Steps

Figure 3-6: Intracellular Ca transient obtained with the bioluminescent dye Indo-1 is shown in the middle of this figure. It reflects the average instantaneous intracellular Ca ion concentration. The L-type Ca channel current modified by voltage clamping is shown in the top panel, and myocyte shortening is shown in the bottom panel. Note the voltage dependence of the Ca current and the parallel changes in both the Ca transient and shortening. (From Williams.8 Reproduced with permission of the publisher.)

Figure 3-6: Intracellular Ca transient obtained with the bioluminescent dye Indo-1 is shown in the middle of this figure. It reflects the average instantaneous intracellular Ca ion concentration. The L-type Ca channel current modified by voltage clamping is shown in the top panel, and myocyte shortening is shown in the bottom panel. Note the voltage dependence of the Ca current and the parallel changes in both the Ca transient and shortening. (From Williams.8 Reproduced with permission of the publisher.)

The amplification of Ca release inherent in CICR occurs because each DHP release channel induces release of Ca from more than one RyR channel (the exact number is unknown) and because of the very large Ca concentration gradient between the SR and the cytoplasm.7-8'16-25 CICR results in an increase in the intracellular Ca concentration from a diastolic value of approximately 0.1 MM to 1 to 10 MM at the peak of the Ca transient. However, the actual amount of Ca released per beat constitutes only a small amount of the total stored (due to the binding proteins). The increase in intracellular Ca concentration is very transient because free Ca ions rapidly bind to the contractile proteins and are also removed from the cytoplasm by the Na-Ca exchanger and a specialized pump, the SR Ca ATPase (SERCA2).

In order for contraction to be turned off (i.e., for relaxation to occur), Ca ions bound to the contractile proteins must be returned to their storage sites in the SR, and the relatively small number that enter during the AP must be transported back to the extracellular space. As indicated earlier, the Na-Ca exchanger is primarily responsible for extrusion of Ca out of the cytoplasm. There is also a sarcolemmal Ca pump that uses energy from ATP hydrolysis, but this does not appear to be an important means of Ca extrusion. The most important mechanism of reuptake of Ca ions by the SR is pumping by SERCA2, a SR membrane-spanning protein7-13-27 (see B+fli Fig. 3-3). SERCA2 uses energy from ATP hydrolysis to rapidly pump the bulk of Ca ions released during CICR back into the SR. It competes with the contractile proteins and other potential uptake sites (Na-Ca exchanger, sarcolemmal ATPase, mitochondria) for Ca ions. Pump stoichiometry is two Ca ions for each ATP hydrolyzed. Functionally, Ca ions pumped back into the SR initially enter a "reuptake pool" and then move to a "release" pool.

The SERCA2 pump is partially self-regulating, since its speed increases in proportion to free Ca concentration (see below). It is also regulated by a closely associated SR protein, phospholamban (PLB), a key modulator of cardiac responses to adrenergic signaling.28-33 PLB is a 52-amino-acid protein with a hydrophobic domain anchored in the SR membrane and a hydrophilic domain containing three phosphorylation sites. PLB inhibits SERCA2 activity, as exemplified by transgenic PLB knockout mice with increased basal cardiac contractility due to increased Ca cycling per beat but blunted adrenergic responses.3^31 f>- Adrenergic stimulation results in phosphorylation of PLB by activation of cyclic AMP-dependent protein kinase A (PKA). This reduces the inhibitory effect of PLB on SERCA2, resulting in increased Ca cycled per beat and an increased reuptake rate. These effects increase the rate and force of contraction as well as relaxation rate. (In addition to PLB phosphorylation, adrenergic stimulation of PKA also causes phosphorylation of L-type Ca channels,815 34 resulting in increased transsarcolemmal Ca current and increased CICR via RyR channels.)

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