T-tubule

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T-tubule
Blausen 0801 SkeletalMuscle.png
Figure 1: Skeletal muscle, with T-tubule labeled in zoomed in image.
1023 T-tubule.jpg
Narrow T-tubules permit the conduction of electrical impulses. The SR functions to regulate intracellular levels of calcium. Two terminal cisternae (where enlarged SR connects to the T-tubule) and one T-tubule comprise a triad—a “threesome” of membranes, with those of SR on two sides and the T-tubule sandwiched in-between them.
Details
Identifiers
Latin tubulus transversus
Code TH H2.00.05.2.01018
TH H2.00.05.2.02013
Anatomical terminology

Transverse tubules (T-tubules) are extensions of the sarcolemma (muscle cell membrane) that penetrate into the centre of skeletal and cardiac muscle cells. T-tubules are highly specialised structures, that form within the first few weeks of life,[1] containing large amounts of specific proteins known as ion channels that allow for electrical impulses (action potentials) travelling along the sarcolemma, to enter rapidly into the cell, to initiate muscle contraction.

Structure[edit]

Each muscle cell is surrounded by a sarcolemma. As T-tubules are simply continuations of the sarcolemma, their membranes are very similar to that of the cell membrane, consisting of two layers of lipid (fat) molecules (known as a lipid bilayer) with proteins, including: L-type calcium channels, sodium-calcium exchangers, calcium ATPases and Beta adrenoceptors, (see below) embedded within.

Despite what their name suggests, transverse-tubules are actually networks of tubules with both transverse (running at a right angle to the sarcolemma) sections, connected by axial/longitudinal tubules. Therefore, they are also known as the transverse-axial tubular system [2] and they run alongside myofilament bundles (proteins that are responsible for muscle contraction).

The shape of the T-tubule system is produced and maintained by a variety of proteins. For example, a protein called Amphyphysin 2 is responsible to forming the structure of the T-tubule as well as ensuring that the appropriate proteins (in particular the L-type calcium channels) are located within the T-tubule membrane. Another example, is junctophilin 2. This protein helps to form a junction between the t-tubule membrane and an intracellular calcium store known as the sarcoplasmic reticulum (SR). This junction is vital for excitation-contraction coupling within muscle cells (see below). A final example is Tcap. Tcap helps with t-tubule development. There has been shown to be increased amounts of Tcap present in response to muscles stretching. This protein is therefore responsible for an increase in the number of t-tubules as muscles grow.[3]

Skeletal and cardiac muscles are known collectively as striated muscles. This is because of their stripey appearance due to the contractile proteins (also known as myofilaments; in paricular actin and myosin) within them.

In cardiac muscle cells, T-tubules are between 20 and 450 nanometers in diameter (nm; 1 nm=0.000000001m) and are usually located in regions called Z-discs (this is where the actin fiilaments (mentioned above) anchor, within the cell).[4] T-tubules within the heart are closely associated with a region of the sarcoplasmic reticulum known as terminal cisternae. This is known as a dyad.

In skeletal muscle cells, T-tubules are between 20 and 40 nm in diameter and are typically located either side of the myosin strip, at the junction overlap between the A and I bands. T-tubules in skeletal muscle are associated with two terminal cisternae. This is known as a triad (see figure 1).[4][5]

Function[edit]

Excitation-contraction coupling[edit]

See Excitation-contraction coupling

T-tubules are the main sites for the coupling of excitation-contraction coupling, which is the process where an action potential, passing along the sarcolemma causes the muscle to contract. As the action potential, passes down the t-tubules, it activates the L-type calcium channels in the t-tubular membrane. In cardiac muscle activation of the L-type calcium channel, results in it forming a pore. This pore allows calcium (Ca2+) to pass into the cell, from outside. This calcium binds to and activates a receptor, known as a ryanodine receptor, which is located on the sarcoplasmic reticulum. The sarcoplasmic reticulum is a calcium store, therefore activation of the ryanodine receptor, and the subsequent opening of the RyR channel, results even more calcium flooding into the cell. This calcium is then used to produce contraction of the muscle.[6]

In skeletal muscle cells, however, the L-type calcium channel is attached To the ryanodine receptor on the SR. Therefore, activation of the L-type calcium channel, directly activates the RyR (without the need for an influx of calcium).[7]

Dyads and triads are, therefore, vital for excitation-contraction coupling as they allow for the L-type calcium channels and ryanodine receptors to be in close proximity, with roughly 12 nm between them.[3]

As the t-tubules are the primary location for excitation-contraction coupling, the ion channels and proteins involved in this process are mainly situated here. For example, there are 3 times as many L-type calcium channels located within the t-tubule membrane, in comparison to the rest of the sarcolemma. Not only that but beta adrenoceptors are also highly concentrated here.[8] Beta adrenoceptors, are receptors that are activated by adrenaline. Adrenaline is a hormone released from the adrenal gland, as part of the bodies fight or flight response. When adrenaline binds to the beta adrenoceptor, it activates it. This activation, simulates a protein called a Gs-protein, which initiates a series of reactions (known as the cyclic AMP pathway), leading to the production of Protein Kinase A (PKA). Protein Kinase A has the ability to add a phosphate to its target. In this instance one of PKAs targets is the RyR. The RyR is bound to a protein called FKBP (FK-506 binding protein), which prevents the RyR from opening. However, when the RyR becomes phosphorylated, by PKA, the FKBP unbinds, meaning that the RyR is more sensitive to stimulation. This means that there is an increased release of calcium from the SR.[9]

As T-tubules and the sarcomplasmic reticulum spread throughout the muscle cells, they allow for synchronised calcium release across the whole cell, as the action potential is travelling so fast, that it activates all of the L-type calcium channels at almost exactly the same time. Therefore, in cells lacking t-tubules (including smooth muscle cells), the calcium that enters at the sarcolemma, has to diffuse gradually throughout the cell, activating the ryanodine receptors as a wave of calcium. This process is a much slower and results in reduced force of contraction.

Calcium control[edit]

As the t-tubular space is continuous with the extracellular space, ion concentrations between the two are very similar. However, due to the importance of the ions within the t-tubules (particularly calcium in cardiac muscle), it is very important that these concentrations remain relatively constant. As the t-tubules are very thin, they essentially trap the ions, this is important as it means that regardless of the ion concentrations elsewhere in the cell, the t-tubules still have enough ions to allow for muscle contraction. So, for example, if extracellular calcium concentration was to fall (this is known as hypocalcaemia), the t-tubule would hold on to the calcium it has. This means that cardiac excitation-contraction coupling can still occur and the heart will continue to beat.[3]

As well as t-tubules being a site for calcium entry into the cell, they are also a site for calcium removal from the cell. This is important as it means that calcium levels within the cell can be tightly controlled in a small area (i.e. between the t-tubule and sarcoplasmic reticulum; this is known as local control).[10] Proteins such as the Sodium(Na+)-Calcium(Ca2+) exchanger, and the sarcolemmal ATPase are located mainly in the t-tubule membrane.[3] Both of these proteins force calcium from areas of lower concentration (i.e. within the cell) to areas of higher concentration (i.e. outside the cell; the difference in concentrations is known as the concentration gradient). This process therefore requires energy, which the proteins get from a molecule called adenosine triphosphate (ATP). The Na+-Ca2+ exchanger works by removing 1 Ca2+ from the cell in exchange for 3Na+, whereas the Ca2+ATPase works by simply removing calcium from the cell.

Remodelling[edit]

The structure of a t-tubule is vital to its function, allowing it to travel deep within the muscle cell and being in close proximity to the sarcoplasmic reticulum. Sometimes, the shape of the T-tubule is lost (it is remodelled).This occurs in the hearts of patients with advanced heart failure and is associated with lower chances of recovery.[11] Structural changes in t-tubules can lead to the L-type calcium channels moving away from the ryanodine receptors, so that they are not in line. This can increase the time taken for calcium levels within the cell to rise and lead to weaker contractions and arrhythmia (irregular heart beat).[3][12]

It has been shown that the structure of remodelled tubules can be reversed, through the use of interval training (alternating between high and low intensity workouts).[3]

Detubulation[edit]

Scientists can uncouple T-tubules from the surface membrane using a technique known as detubulation. This relies on chemicals, such as glycerol[13] (for skeletal muscle) or formamide[14] (mainly for cardiac muscle), which are used due to the fact that they can't freely move across the membrane (i.e. they are osmotically active). Addition of these chemicals to the solution surrounding muscle cells causes the cells to shrink. When the chemical is withdrawn, the cells rapidly expand before returning to their normal size. It is the rapid expansion that causes the t-tubules to detach from the surface membrane. This technique can be used to investigate the function of the t-tubules.

See also[edit]

References[edit]

  1. ^ Haddock, Peter S.; Coetzee, William A.; Cho, Emily; Porter, Lisa; Katoh, Hideki; Bers, Donald M.; Jafri, M. Saleet; Artman, Michael (1999-09-03). "Subcellular [Ca2+]i Gradients During Excitation-Contraction Coupling in Newborn Rabbit Ventricular Myocytes". Circulation Research. 85 (5): 415–427. ISSN 0009-7330. PMID 10473671. doi:10.1161/01.RES.85.5.415. 
  2. ^ Ferrantini, Cecilia; Coppini, Raffaele; Sacconi, Leonardo; Tosi, Benedetta; Zhang, Mei Luo; Wang, Guo Liang; Vries, Ewout de; Hoppenbrouwers, Ernst; Pavone, Francesco (2014-06-01). "Impact of detubulation on force and kinetics of cardiac muscle contraction". The Journal of General Physiology. 143 (6): 783–797. PMC 4035744Freely accessible. PMID 24863933. doi:10.1085/jgp.201311125. 
  3. ^ a b c d e f Ibrahim, M.; Gorelik, J.; Yacoub, M. H.; Terracciano, C. M. (2011-09-22). "The structure and function of cardiac t-tubules in health and disease". Proceedings of the Royal Society B: Biological Sciences. 278 (1719): 2714–2723. PMC 3145195Freely accessible. PMID 21697171. doi:10.1098/rspb.2011.0624. 
  4. ^ a b Hong, TingTing; Shaw, Robin M. (2017-01-01). "Cardiac T-Tubule Microanatomy and Function". Physiological Reviews. 97 (1): 227–252. ISSN 0031-9333. PMID 27881552. doi:10.1152/physrev.00037.2015. 
  5. ^ "4. Calcium reuptake and relaxation.". www.bristol.ac.uk. Retrieved 2017-02-21. 
  6. ^ Bers, Donald M. (2002-01-10). "Cardiac excitation-contraction coupling". Nature. 415 (6868): 198–205. ISSN 0028-0836. PMID 11805843. doi:10.1038/415198a. 
  7. ^ Rebbeck, Robyn T.; Karunasekara, Yamuna; Board, Philip G.; Beard, Nicole A.; Casarotto, Marco G.; Dulhunty, Angela F. (2014-03-01). "Skeletal muscle excitation-contraction coupling: who are the dancing partners?". The International Journal of Biochemistry & Cell Biology. 48: 28–38. ISSN 1878-5875. PMID 24374102. doi:10.1016/j.biocel.2013.12.001. 
  8. ^ Laflamme, M. A.; Becker, P. L. (1999-11-01). "G(s) and adenylyl cyclase in transverse tubules of heart: implications for cAMP-dependent signaling". The American Journal of Physiology. 277 (5 Pt 2): H1841–1848. ISSN 0002-9513. PMID 10564138. 
  9. ^ Bers, Donald M. (2006-05-15). "Cardiac ryanodine receptor phosphorylation: target sites and functional consequences". Biochemical Journal. 396 (Pt 1): e1. ISSN 0264-6021. PMC 1450001Freely accessible. PMID 16626281. doi:10.1042/BJ20060377. 
  10. ^ Hinch, R., Greenstein, J.L., Tanskanen, A.J., Xu, L. and Winslow, R.L. (2004) ‘A simplified local control model of calcium-induced calcium release in cardiac ventricular Myocytes’, 87(6).
  11. ^ Seidel, Thomas; Navankasattusas, Sutip; Ahmad, Azmi; Diakos, Nikolaos A.; Xu, Weining David; Tristani-Firouzi, Martin; Bonios, Michael J.; Taleb, Iosif; Li, Dean Y. (2017-04-25). "Sheet-Like Remodeling of the Transverse Tubular System in Human Heart Failure Impairs Excitation-Contraction Coupling and Functional Recovery by Mechanical Unloading". Circulation. 135 (17): 1632–1645. ISSN 1524-4539. PMC 5404964Freely accessible. PMID 28073805. doi:10.1161/CIRCULATIONAHA.116.024470. 
  12. ^ Crossman DJ, Young AA, Ruygrok PN, Nason GP, Baddelely D, Soeller C, Cannell MB (May 2015). "t-tubule disease: Relationship between t-tubule organization and regional contractile performance in human dilated cardiomyopathy". Journal of Molecular and Cellular Cardiology. 84: 170–8. PMC 4467993Freely accessible. PMID 25953258. doi:10.1016/j.yjmcc.2015.04.022. 
  13. ^ Fraser, James A.; Skepper, Jeremy N.; Hockaday, Austin R.; Huang1, Christopher L.-H. (1998-08-01). "The tubular vacuolation process in amphibian skeletal muscle". Journal of Muscle Research & Cell Motility. 19 (6): 613–629. ISSN 0142-4319. doi:10.1023/A:1005325013355. 
  14. ^ Ferrantini, Cecilia; Coppini, Raffaele; Sacconi, Leonardo; Tosi, Benedetta; Zhang, Mei Luo; Wang, Guo Liang; de Vries, Ewout; Hoppenbrouwers, Ernst; Pavone, Francesco (2014-06-01). "Impact of detubulation on force and kinetics of cardiac muscle contraction". The Journal of General Physiology. 143 (6): 783–797. ISSN 1540-7748. PMC 4035744Freely accessible. PMID 24863933. doi:10.1085/jgp.201311125. 

External links[edit]