Sarcoplasmic reticulum


The sarcoplasmic reticulum is a membrane-bound structure found within muscle cells that is similar to the endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions. Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell. This means that small increases in calcium ions within the cell are easily detected and can bring about important cellular changes. Calcium is used to make calcium carbonate and calcium phosphate, two compounds that the body uses to make teeth and bones. This means that too much calcium within the cells can lead to hardening of certain intracellular structures, including the mitochondria, 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 tubules that extend throughout muscle cells, wrapping around the myofibrils. Cardiac and skeletal muscle cells contain structures called transverse tubules, which are extensions of the cell membrane that travel into the centre of the cell. T-tubules are closely associated with a specific region of the SR, known as the terminal cisternae in skeletal muscle, with a distance of roughly 12 nanometers, separating them. This is the primary site of calcium release. The longitudinal SR are thinner projects, that run between the terminal cisternae/junctional SR, and are the location where ion channels necessary for calcium ion absorption are most abundant. These processes are explained in more detail below and are fundamental for the process of excitation-contraction coupling in skeletal, cardiac and 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 won't freely flow into the SR, and therefore pumps are required, that use energy, which they gain from a molecule called adenosine triphosphate. These calcium pumps are called Sarcoplasmic reticulum ATPases. There are a variety of different forms of SERCA, with SERCA 2a being found primarily in cardiac and skeletal muscle.
SERCA consists of 13 subunits. Calcium ions bind to the M1-M10 subunits, whereas ATP binds to the N, P and A subunits. When 2 calcium ions, along with a molecule of ATP, bind to the cytosolic side of the pump, the pump opens. This occurs because ATP releases a single phosphate group. The released phosphate group then binds to the pump, 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.
A protein found in cardiac muscle, called phospholamban has been shown to prevent SERCA from working. It does this by binding to the SERCA and decreasing its attraction to calcium, therefore preventing calcium uptake into the SR. Failure to remove Ca2+ from the cytosol, prevents muscle relaxation and therefore means that there is a decrease in muscle contraction too. However, molecules such as adrenaline and 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 that produces an enzyme called protein kinase A. PKA can add a phosphate to PLB, preventing it from inhibiting SERCA and allowing for muscle relaxation.

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. Therefore, more calcium can be stored. It is primarily located within the junctional SR/terminal cisternae, in close association with the calcium release channel.

Calcium release

Calcium ion release from the SR, occurs in the junctional SR/terminal cisternae through a ryanodine receptor and is known as a calcium spark. There are three types of ryanodine receptor, RyR1, RyR2 and RyR3. Calcium release through ryanodine receptors in the SR is triggered differently in different muscles. In cardiac and smooth muscle an electrical impulse triggers calcium ions to enter the cell through an L-type calcium channel located in the cell membrane or T-tubule membrane. 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. Also, caffeine can bind to and stimulate RyR. Caffeine makes the RyR more sensitive to either the action potential or calcium, thereby producing calcium sparks more often.
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 to the ryanodine receptor. At ‘normal’ SR calcium levels, calsequestrin binds to the RyR, Triadin and Junctin, which prevents the RyR from opening. 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.
In addition to the effects that PKA had on phospholamban that resulted in increased relaxation of the cardiac muscle, PKA can also 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. Therefore, in cardiac muscle, activation of PKA, through the cyclic AMP pathway, results in increased muscle contraction and increased relaxation, 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, or the ryanodine receptors becoming inactive after a calcium spark, while others believe that a decrease in SR calcium, triggers the receptors to close.

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.
If the concentration of calcium increases in the sarcoplasm then it can also cause muscles stiffness.