Sarcoplasmic reticulum

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A cartoon section of skeletal muscle, showing T-tubules running deep into the centre of the cell between two terminal cisternae/junctional SR. The thinner projections, running horizontally between two terminal cisternae are the longitudinal sections of the SR.

The sarcoplasmic reticulum (SR) is a

teeth and bones. This means that too much calcium within the cells can lead to hardening (calcification) of certain intracellular structures, including the mitochondria,[2]
leading to cell death. Therefore, it is vital that calcium ion levels are controlled tightly, and can be released into the cell when necessary and then removed from the cell.

Structure

The sarcoplasmic reticulum is a network of the tubules that extend throughout

smooth muscle
.

Calcium absorption

The SR contains ion channel pumps, within its membrane that are responsible for pumping Ca2+ into the SR. As the calcium ion concentration within the SR is higher than in the rest of the cell, the calcium ions will not freely flow into the SR, and therefore pumps are required, that use energy, which they gain from a molecule called adenosine triphosphate (ATP). These calcium pumps are called Sarco(endo)plasmic reticulum Ca2+ ATPases (SERCA). There are a variety of different forms of SERCA, with SERCA 2a being found primarily in cardiac and skeletal muscle.[5]

SERCA consists of 13 structural elements (labelled M1-M10 α-helices in the transmembrane domain, and N, P and A citosolic domains). Calcium ions bind to the M1-M10 transmembrane region, whereas ATP binds to the N domain. When 2 calcium ions, along with a molecule of ATP, bind to the cytosolic side of the pump (i.e. the region of the pump outside the SR), the pump opens. This occurs because ATP (which contains three phosphate groups) releases a single phosphate group (becoming adenosine diphosphate). The released phosphate group then binds to the pump (in the P domain), causing the pump to change shape. This shape change causes the cytosolic side of the pump to open, allowing the two Ca2+ to enter. The cytosolic side of the pump then closes and the sarcoplasmic reticulum side opens, releasing the Ca2+ into the SR.[6]

A

noradrenaline, can prevent PLB from inhibiting SERCA. When these hormones bind to a receptor, called a beta 1 adrenoceptor, located on the cell membrane, they produce a series of reactions (known as a cyclic AMP pathway) that produces an enzyme called protein kinase A (PKA). PKA can add a phosphate to PLB (this is known as phosphorylation), preventing it from inhibiting SERCA and allowing for muscle relaxation.[7]

Calcium storage

Located within the SR is a protein called calsequestrin. This protein can bind to around 50 Ca2+, which decreases the amount of free Ca2+ within the SR (as more is bound to calsequestrin).[8] Therefore, more calcium can be stored (the calsequestrin is said to be a buffer). It is primarily located within the junctional SR/luminal space, in close association with the calcium release channel (described below).[9]

Calcium release

Calcium ion release from the SR, occurs in the junctional SR/

RyR3 (in the brain).[11] Calcium release through ryanodine receptors in the SR is triggered differently in different muscles. In cardiac and smooth muscle an electrical impulse (action potential) triggers calcium ions to enter the cell through an L-type calcium channel located in the cell membrane (smooth muscle) or T-tubule membrane (cardiac muscle). These calcium ions bind to and activate the RyR, producing a larger increase in intracellular calcium. In skeletal muscle, however, the L-type calcium channel is bound to the RyR. Therefore, activation of the L-type calcium channel, via an action potential, activates the RyR directly, causing calcium release (see calcium sparks for more details).[12] Also, caffeine (found in coffee) can bind to and stimulate RyR. Caffeine makes the RyR more sensitive to either the action potential (skeletal muscle) or calcium (cardiac or smooth muscle), thereby producing calcium sparks more often (this is partially responsible for caffeine's effect on heart rate).[13]

Triadin and Junctin are proteins found within the SR membrane, that are bound to the RyR. The main role of these proteins is to anchor calsequestrin (see above) to the ryanodine receptor. At ‘normal’ (physiological) SR calcium levels, calsequestrin binds to the RyR, Triadin and Junctin, which prevents the RyR from opening.[14] If calcium concentration within the SR falls too low, there will be less calcium bound to the calsequestrin. This means that there is more room on the calsequestrin, to bind to the junctin, triadin and ryanodine receptor, therefore it binds tighter. However, if calcium within the SR rises too high, more calcium binds to the calsequestrin and therefore it binds to the junctin-triadin-RyR complex less tightly. The RyR can therefore open and release calcium into the cell.[15]

In addition to the effects that PKA had on

phosphorylate ryanodine receptors. When phosphorylated, RyRs are more sensitive to calcium, therefore they open more often and for longer periods of time. This increases calcium release from the SR, increasing the rate of contraction.[16] Therefore, in cardiac muscle, activation of PKA, through the cyclic AMP pathway, results in increased muscle contraction (via RyR2 phosphorylation) and increased relaxation (via phospholamban
phosphorylation), which increases heart rate.

The mechanism behind the termination of calcium release through the RyR is still not fully understood. Some researchers believe it is due to the random closing of ryanodine receptors (known as stochastic attrition), or the ryanodine receptors becoming inactive after a calcium spark,[17] while others believe that a decrease in SR calcium, triggers the receptors to close (see calcium sparks for more details).

Role in rigor mortis

The breakdown of the sarcoplasmic reticulum, along with the resultant release of calcium, is an important contributor to rigor mortis, the stiffening of muscles after death.

An increase in calcium concentration in the sarcoplasm can also cause muscle stiffness.

References

  1. ^ Bronner, F. (2003) ‘Extracellular and intracellular regulation of calcium homeostasis’, TheScientificWorldJournal., 1, pp. 919–25.
  2. ^ Trump, B., Berezesky, I., Laiho, K., Osornio, A., Mergner, W. and Smith, M. (1980) ‘The role of calcium in cell injury. A review’, Scanning electron microscopy., pp. 437–62.
  3. ^ The anatomy of the sarcoplasmic reticulum in vertebrate skeletal muscle: Its implications for excitation contraction coupling’, Zeitschrift für Naturforschung. Section C, Biosciences., 37, pp. 665–78.
  4. PMID 8137493
    .
  5. ^ Periasamy, M. and Kalyanasundaram, A. (2007) ‘SERCA pump isoforms: Their role in calcium ion transport and disease’, Muscle & Nerve, 35(4), pp. 430–42.
  6. ^ Kekenes-Huskey, P.M., Metzger, V.T., Grant, B.J. and McCammon, A.J. (2012b) ‘Calcium binding and allosteric signaling mechanisms for the sarcoplasmic reticulum Ca2+ ATPase’, 21(10).
  7. ^ Akin, B., Hurley, T., Chen, Z. and Jones, L. (2013) ‘The structural basis for phospholamban inhibition of the calcium pump in sarcoplasmic reticulum’, The Journal of Biological Chemistry., 288(42), pp. 30181–91.
  8. PMID 15050380
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  9. ^ Kobayashi, Y. M.; Alseikhan, B. A.; Jones, L. R. (2000): Localization and characterization of the calsequestrin-binding domain of triadin 1. Evidence for a charged beta-strand in mediating the protein-protein interaction. In The Journal of biological chemistry 275 (23), pp. 17639–17646. DOI: 10.1074/jbc.M002091200.
  10. PMID 8235594
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  11. ^ Lanner, J.T., Georgiou, D.K., Joshi, A.D. and Hamilton, S.L. (2010b) ‘Ryanodine receptors: Structure, expression, molecular details, and function in calcium release’, 2(11).
  12. ^ Cheng, H. and Lederer, W. (2008) ‘Calcium sparks’, Physiological Reviews., 88(4), pp. 1491–545.
  13. ^ Sitsapesan R, Williams AJ. Mechanisms of caffeine activation of single calcium-release channels of sheep cardiac sarcoplasmic reticulum. J Physiol (Lond) 1990;423:425– 439]
  14. PMID 9287354
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  15. ^ Györke, I., Hester, N., Jones, L.R. and Györke, S. (2004) ‘The role of Calsequestrin, Triadin, and Junctin in conferring cardiac Ryanodine receptor responsiveness to Luminal calcium’, 86(4).
  16. ^ Bers, D.M. (2006) ‘Cardiac ryanodine receptor phosphorylation: Target sites and functional consequences’, 396(1).
  17. PMID 9844021
    .
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