Full Answer
Why is SR important in smooth muscle?
The SR is vital to the modulation and regulation of force in smooth muscles. Pathophysiologies are associated with perturbation of SERCA, Ca release mechanisms, and regulatory proteins, but our appreciation of this lags behind studies on striated muscles. This can largely be attributed to the lack of clarity around the regulation of normal SR function in smooth muscle, which in turn is affected by genuine differences between tissues. It is uncommon for investigators to address more than one smooth muscle in their studies, leading to pockets of detailed information in specific areas, but a lack of breadth. There are areas where real progress has been made, such as unraveling the Ca spark-STOC mechanism of regulating excitability and function. Other areas remain controversial, such as the role of TRPCs in store-operated Ca entry. A key question remaining to be answered is whether in smooth muscle SR Ca depletion leads to Icrac only through the Stim-Orai pathway. Another key question is how important SOCE is to those smooth muscles whose main source of Ca for contraction is L-type Ca entry; need such mechanisms be required if SERCA can refill from the plasmalemmal Ca entry? More measurements of SR luminal Ca are also required, as they could provide important mechanistic insight.
What organelle stores Ca?
Interest in lysosomes as Ca storage organelles was stimulated by the finding that in sea urchin eggs a recently identified new Ca mobilizer, nicotinic acid adenine dinucleotide phosphate (NAADP), was stored in organelles equivalent to lysosomes in mammalian cells ( 126 ). NAADP is discussed further in section v. In smooth muscle, a close association between the SR and perinuclear lysosomes has been shown ( 350, 650 ), and this region is described as a “trigger zone.” Lysosomes are acidic organelles dependent on vacuolar H-ATPase activity. Drugs that inhibit the transporter, such as bacliomycin, have therefore been used to determine the importance of this Ca store to cells in which this type of Ca mobilizer has been found [myometrial ( 650 ), pulmonary ( 61 ), and coronary myocytes ( 800 )]. In these studies a decrease in the Ca signal to agonists (endothelin-1, histamine) was found. To date, no studies in smooth muscle have tried to assess the size of the lysosomal Ca pool or looked at the dynamics of its interaction with the SR. It appears at least in some cells that the NAADP release can trigger SR Ca release from RyRs, but not IP 3 R, suggesting a clustering of RyRs with the release channels on the lysosomes ( 61 ).
Where are ryrs expressed?
Each of the three isoforms of RyRs are encoded by a distinct gene (670). RyR1 and RyR2 are predominantly expressed in skeletal (812) and cardiac (532, 599) muscle , respectively, while RyR3 appears to be expressed in a variety of tissues (211, 243, 389).
Where is the gene for serac2b?
SERCA2 is 84% identical in sequence to SERCA1a. The gene for SERCA2 is located on human chromosome 12 at 12q24.11. SERCA2b has a longer (luminal) COOH-terminal tail than that of SERCA2a, which is cytoplasmic ( 726 ). SERCA2a is expressed in heart, slow-twitch skeletal muscle, and many types of smooth muscles ( 25 ). SERCA2b appears be ubiquitously expressed, leading to it being labeled as the housekeeping form of SERCA. This designation, while also consistent with it being the phylogenetically earliest isoform, is likely to be too simplistic, as different tissues express different levels of SERCA2b ( 777 ). From expression studies in COS and cardiac cells it has been suggested that, compared with SERCA2a, the 2b isoform has a lower turnover rate of ATP hydrolysis, a 10-fold lower vanadate sensitivity and Ca transport rate, but a higher apparent affinity for Ca ( 425, 723, 724 ). Removal of the last 12 amino acids from SERCA2b in mouse cardiac cells abolished these differences, suggesting the long tail in 2b is affecting SERCA activity ( 723 ). Another difference between SERCA2a and -2b is the greater stability of 2a's mRNA, perhaps explaining its increased expression levels. Both isoforms have the same sensitivity to phospholamban and thapsigargin ( 426 ).
What is the simplest catalytic cycle for SERCA?
The simplest catalytic cycle for SERCA can be described as follows: E 1 →2Ca-E 1 ,→2Ca-E 1 -ATP→2Ca-E 1 ∼P i →2Ca-E 2 -P i →E 2 -P i →E 2 →E 1 (see also Fig. 4 ).
What is the role of serac in ATPase?
SERCA is the major protein associated with the SR. It is a P-type ATPase responsible for transporting Ca into the SR at the expense of ATP. Calcium binding proteins enable this process to continue with an SR free ionized Ca content of ∼500 μM, only ∼0.5–1% of the total Ca stored in the SR ( 463 ). This sequestering of luminal Ca also means that inhibitory feedback of Ca on the ATPase is minimized. Auxiliary proteins, most notably phospholamban, as well as metabolites and pH, regulate SERCA activity. Several isoforms of SERCA exist, and expression varies between smooth muscles.
Which protein is a homolog of phospholamban?
D. Sarcolipin . This 31-amino acid protein appears to be a homolog of phospholamban (522); it associates with the SR membrane, and its transmembrane domains are structurally similar. Sarcolipin inhibits SERCA by lowering its apparent Ca affinity (increasing Km) and Vmax(27, 205, 435, 523).
What is the role of calcium in muscle contraction?
By regulating the concentration of calcium in the sarcoplasm (the cytoplasm of striated muscle cells), the sarcoplasmic reticulum plays an important role in determining whether muscle contraction occurs. In cardiac muscle cells, calcium is an important effector of the coupling between cardiac depolarization (excitation) and cardiac contraction ...
Why is reabsorption of calcium by the sarcoplasmic reticulum important?
Reabsorption of cellular calcium by the sarcoplasmic reticulum is important because it prevents the development of muscle tension. In the resting state, two proteins, troponin and tropomyosin, bind to actinmolecules and inhibitinteraction between actin and myosin, thereby blocking muscle contraction. When calcium concentration increases during depolarization, it shifts the conformation of troponin and tropomyosin, and actin is able to associate with myosin. As calcium is taken up again by the sarcoplasmic reticulum the muscle cell relaxes.
What is the sarcoplasmic reticulum?
Sarcoplasmic reticulum, intracellular system of closed saclike membranes involved in the storage of intracellular calcium in striated (skeletal) muscle cells. Each segment of the sarcoplasmic reticulum forms a cufflike structure surrounding a myofibril, the fine contractile fibres that extend the length of striated muscle cells.
What happens to the calcium in the heart when the heart is repolarized?
When the heart is repolarized, the sarcoplasmic reticulum reabsorbs the excess calcium, and the cellular calcium concentration returns ...
What happens to the calcium concentration during depolarization?
When calcium concentration increases during depolarization, it shifts the conformation of troponin and tropomyosin, and actin is able to associate with myosin. As calcium is taken up again by the sarcoplasmic reticulum the muscle cell relaxes.
What is the effect of calcium on cardiac muscle?
In cardiac muscle cells, calcium is an important effector of the coupling between cardiac depolarization (excitation) and cardiac contraction (called “excitation-contraction coupling”). In these cells, the sarcoplasmic reticulum sequesters calcium ions and thereby maintains low calcium concentrations in the sarcoplasm.
Why is repolarization important for the heart?
When the heart is repolarized, the sarcoplasmic reticulum reabsorbs the excess calcium, and the cellular calcium concentration returns to its formerly low level, letting the heart muscle relax. Reabsorption of cellular calcium by the sarcoplasmic reticulum is important because it prevents the development of muscle tension.
What protein prevents SERCA from working?
A protein found in cardiac muscle, called phospholamban (PLB) has been shown to prevent SERCA from working. It does this by binding to the SERCA and decreasing its attraction (affinity) to calcium, therefore preventing calcium uptake into the SR.
What is the function of the sarcoplasmic reticulum?
The main function of the SR is to store calcium ions (Ca 2+ ). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller ...
Why does calcium release stop?
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, while others believe that a decrease in SR calcium, triggers the receptors to close (see calcium sparks for more details).
What are the subunits of the SERCA?
SERCA consists of 13 subunits (labelled M1-M10, N, P and A). Calcium ions bind to the M1-M10 subunits (which are located within the membrane), whereas ATP binds to the N, P and A subunits (which are located outside the SR). 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, causing the pump to change shape. This shape change causes the cytosolic side of the pump to open, allowing the two Ca 2+ to enter. The cytosolic side of the pump then closes and the sarcoplasmic reticulum side opens, releasing the Ca 2+ into the SR.
What is the SR pump?
The SR contains ion channel pumps, within its membrane that are responsible for pumping Ca 2+ 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 (ATP). These calcium pumps are called Sarco (endo)plasmic reticulum Ca 2+ ATPases (SERCA). There are a variety of different forms of SERCA, with SERCA 2a being found primarily in cardiac and skeletal muscle.
What causes stiffness in the sarcoplasm?
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.
Where does calcium ion release occur?
Calcium ion release from the SR, occurs in the junctional SR/ terminal cisternae through a ryanodine receptor (RyR) and is known as a calcium spark. There are three types of ryanodine receptor, RyR1 (in skeletal muscle ), RyR2 (in cardiac muscle) and RyR3 (in the brain ). 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). 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).
What protein binds to tropomyosin?
Calcium binds to this protein, causing shape change that moves tropomyosin
What is a single beat of the heart?
a. a single beat of the heart results from the propagation of a single action potential
What causes force generation and sliding of thick and thin filaments?
e. Cross-bridge binding causes force generation and sliding of thick and thin filaments.
Which receptor allows both Na+ and K+ to diffuse through the muscle cell membrane?
b. The opening of the ligand-gated receptor allows both Na+ and K+ to diffuse through the muscle cell membrane
Which molecule binds to troponin?
a. Ca2+ binds to troponin, causing tropomyosin to move away from cross-bridge binding sites on actin
Where are action potentials initiated?
d. action potentials are initiated in cardiac muscle by autonomic neurons, at the neuromuscular junctions
Which tubules carry the action potential through the sarcoplasm?
T tubules carry the action potential through the sarcoplasm.
Which nerve fiber innervates all muscle fibers?
All of the muscle fibers innervated by a single motor nerv e fiber
