Cardiac excitation-contraction coupling

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Cardiac excitation-contraction coupling (CardiacEC coupling) describes the series of events, from the production of an electrical impulse (action potential) to the contraction of muscles in the heart. [1] This process is of vital importance as it allows for the heart to beat in a controlled manner, without the need for conscious input. EC coupling results in the sequential contraction of the heart muscles that allows blood to be pumped, first to the lungs (pulmonary circulation) and then around the rest of the body (systemic circulation) at a rate between 60 and 100 beats every minute, when the body is at rest. [2] This rate can be altered, however, by nerves that work to either increase heart rate (sympathetic nerves) or decrease it (parasympathetic nerves), as the body's oxygen demands change. Ultimately, muscle contraction revolves around a charged atom (ion), calcium (Ca2+), [3] which is responsible for converting the electrical energy of the action potential into mechanical energy (contraction) of the muscle. This is achieved in a region of the muscle cell, called the transverse tubule during a process known as calcium induced calcium release. [4]

Contents

Initiation

Located in the wall of the right atrium is a group of specialised cells, called the Sinoatrial node (SAN). These cells, unlike most other cells within the heart, can spontaneously produce action potentials. [5] These action potentials travel along the cell membrane (sarcolemma), as impulses, passing from one cell to the next through channels, in structures known as gap junctions. [6]

Calcium-induced calcium release

Certain regions of the sarcolemma penetrate deep into the cell. These are known as transverse-tubules (t-tubules), which are also found in skeletal muscle cells and allow for the action potential to travel into the centre of the cell. [7] Special proteins called L-type calcium channels (also known as dihydropyridine receptors (DHPR)) are located on the t-tubule membrane and are activated by the action potential. Activated DHPRs open, forming a channel that allows Ca2+ to pass into the cell. This increase in Ca2+ then binds to and activates another receptor, called a type 2 ryanodine receptor (RyR2), located on the membrane of a structure known as the sarcoplasmic reticulum (SR). The SR is a Ca2+ stored within the cell and is located very close to the T-tubule. Activation of RyR2 causes it to open, releasing even more Ca2+ into the cell. This release of calcium is called a calcium spark. The initial flow of Ca2+ into the cell causes a larger release of Ca2+ within the cell, so therefore the process is called calcium induced calcium release (CICR). [8]

Muscle Contraction

Figure 1: Calcium binding to troponin, exposes sites on the actin filaments, to which myosin binds. Using ATP, myosin moves the actin along. The myosin releases the actin, resets itself and binds to another actin binding site. 1008 Skeletal Muscle Contraction.jpg
Figure 1: Calcium binding to troponin, exposes sites on the actin filaments, to which myosin binds. Using ATP, myosin moves the actin along. The myosin releases the actin, resets itself and binds to another actin binding site.

The increase in Ca2+, produced by CICR, now does two things. Firstly, it binds to the intracellular side of the DHPR, signalling the channels to close and preventing further influx of Ca2+ into the cell. Secondly Ca2+ indirectly activates proteins, called myofilaments, resulting in muscle contraction. The two main myofilaments in cardiac (and skeletal) muscle are actin and myosin. Ca2+ binds to a protein called troponin, which is bound to the actin filament. This binding causes a shape change in the troponin which exposes areas on the actin, to which the head of the myosin filament binds. The binding of the myosin head to actin is known as a cross-bridge. A molecule, called adenosine triphosphate (ATP) which is produced by an intracellular structure called a mitochondrion, is then used, as a source of energy, to help move the myosin head, carrying the actin. As a result, the actin slides across the myosin filament shortening the muscle. This is called a power stroke. Myosin then detaches from the actin and resets itself back to its original position, binding to another part of the actin and producing another power stroke, shortening the muscle further. This process continues, with the myosin head moving in a motion similar to that of an oar rowing a boat, until the Ca2+ level within the cell decreases (see figure 1). [9]

Termination of contraction

Contraction ends when the Ca2+ is removed from the cell. When this happens, the troponin changes back to its original shape, blocking the binding sites on actin and preventing the formation of crossbridges. This decrease in Ca2+ within the cell is brought about by a variety of proteins, known collectively as ion transporters. The main pumps involved are: the sarcoplasmic reticulum Ca2+-ATPase, which pumps Ca2+ back into the SR, the Sarcolemmal sodium-calcium exchanger, which pumps one Ca2+ out of the cell, in exchange for 3 sodium ions being pumped into the cell, the Sarcolemmal Ca2+-ATPase, which uses ATP to pump Ca2+ directly out of the cell and the Mitochondrial Ca2+ Uniport system, which pumps Ca2+ into the mitochondria. [10]

Heart rate

Sympathetic nerves work by releasing a protein (neurotransmitter) called noradrenaline which binds to a specific receptor (beta 1 adrenoceptor) located in the sarcolemma and the t-tubule membrane of cardiac cells. This activates a protein, called a G-protein and results in a series of reactions (known as a cyclic AMP pathway) that leads to the production of a molecule called cAMP (cyclic adenosine monophosphate). In the SAN cAMP binds to an ion channel involved in action potential initiation, speeding up the production of the action potential (see sinoatrial node for more detail). cAMP also, activates a protein called protein kinase A (PKA). PKA affects both the L-type calcium channels (also known as dihydropyridine receptors (DHPR)) and RyR, increasing the rise in Ca 2+ within the contractile cells and therefore increasing rate of muscle contraction. PKA also affects the myofilaments as well as a protein called phospholamban (PLB; see sarcoplasmic reticulum for more details), speeding up the rate of Ca2+decline in the cell and so speeding up muscle relaxation. [2]

Parasympathetic nerves work by releasing a neurotransmitter called acetylcholine (ACh) which binds to specific receptor (M2 muscarinic receptor) on the sarcolemma of both SAN cells and ventricular cells. This again activates a G-protein. However this G-protein works by inhibiting, the cAMP pathway, therefore, preventing the sympathetic nervous system from increasing heart rate. As well as this, in the SAN, the G-protein activates specific potassium channel, that opposes action potential initiation (see SAN for more details), thus slowing heart rate. [2]

Related Research Articles

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Smoothmuscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non-striated, so-called because it has no sarcomeres and therefore no striations. It can be divided into two subgroups, single-unit and multi-unit smooth muscle. Within single-unit muscle, the whole bundle or sheet of smooth muscle cells contracts as a syncytium.

<span class="mw-page-title-main">Skeletal muscle</span> One of three major types of muscle

Skeletal muscle is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the voluntary muscular system and typically are attached by tendons to bones of a skeleton. The skeletal muscle cells are much longer than in the other types of muscle tissue, and are also known as muscle fibers. The tissue of a skeletal muscle is striated – having a striped appearance due to the arrangement of the sarcomeres.

<span class="mw-page-title-main">Myofibril</span> Contractile element of muscle

A myofibril is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as muscle fibers, and these cells contain many chains of myofibrils. Each myofibril has a diameter of 1–2 micrometres. They are created during embryonic development in a process known as myogenesis.

<span class="mw-page-title-main">Sarcomere</span> Repeating unit of a myofibril in a muscle cell

A sarcomere is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells which are formed during embryonic myogenesis. Muscle fibers contain numerous tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as alternating dark and light bands. Sarcomeres are composed of long, fibrous proteins as filaments that slide past each other when a muscle contracts or relaxes. The costamere is a different component that connects the sarcomere to the sarcolemma.

<span class="mw-page-title-main">Sarcoplasmic reticulum</span> Menbrane-bound structure in muscle cells for storing calcium

The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). 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 (the calcium is said to be a second messenger). Calcium is used to make calcium carbonate (found in chalk) 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 (calcification) 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.

<span class="mw-page-title-main">Cardiac muscle</span> Muscular tissue of heart in vertebrates

Cardiac muscle is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of the heart. The cardiac muscle (myocardium) forms a thick middle layer between the outer layer of the heart wall and the inner layer, with blood supplied via the coronary circulation. It is composed of individual cardiac muscle cells joined by intercalated discs, and encased by collagen fibers and other substances that form the extracellular matrix.

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<span class="mw-page-title-main">Sinoatrial node</span> Group of cells located in the wall of the right atrium of the heart

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<span class="mw-page-title-main">Striated muscle tissue</span> Muscle tissue with repeating functional units called sarcomeres

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<span class="mw-page-title-main">Cardiac action potential</span> Biological process in the heart

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<span class="mw-page-title-main">Muscle contraction</span> Activation of tension-generating sites in muscle

Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as when holding something heavy in the same position. The termination of muscle contraction is followed by muscle relaxation, which is a return of the muscle fibers to their low tension-generating state.

<span class="mw-page-title-main">Calcium signaling</span> Intracellular communication process

Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins. Ca2+ can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.

<span class="mw-page-title-main">T-tubule</span> Extensions in cell membrane of muscle fibres

T-tubules are extensions of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells. With membranes that contain large concentrations of ion channels, transporters, and pumps, T-tubules permit rapid transmission of the action potential into the cell, and also play an important role in regulating cellular calcium concentration.

Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. It is the maximum attainable value for the force of contraction of a given heart. The ability to produce changes in force during contraction result from incremental degrees of binding between different types of tissue, that is, between filaments of myosin (thick) and actin (thin) tissue. The degree of binding depends upon the concentration of calcium ions in the cell. Within an in vivo intact heart, the action/response of the sympathetic nervous system is driven by precisely timed releases of a catecholamine, which is a process that determines the concentration of calcium ions in the cytosol of cardiac muscle cells. The factors causing an increase in contractility work by causing an increase in intracellular calcium ions (Ca++) during contraction.

<span class="mw-page-title-main">Myofilament</span> The two protein filaments of myofibrils in muscle cells

Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the contractile proteins and titin is an elastic protein. The myofilaments act together in muscle contraction, and in order of size are a thick one of mostly myosin, a thin one of mostly actin, and a very thin one of mostly titin.

<span class="mw-page-title-main">Milrinone</span> Chemical compound

Milrinone, sold under the brand name Primacor, is a pulmonary vasodilator used in patients who have heart failure. It is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility and decrease pulmonary vascular resistance. Milrinone also works to vasodilate which helps alleviate increased pressures (afterload) on the heart, thus improving its pumping action. While it has been used in people with heart failure for many years, studies suggest that milrinone may exhibit some negative side effects that have caused some debate about its use clinically.

A calcium spark is the microscopic release of calcium (Ca2+) from a store known as the sarcoplasmic reticulum (SR), located within muscle cells. This release occurs through an ion channel within the membrane of the SR, known as a ryanodine receptor (RyR), which opens upon activation. This process is important as it helps to maintain Ca2+ concentration within the cell. It also initiates muscle contraction in skeletal and cardiac muscles and muscle relaxation in smooth muscles. Ca2+ sparks are important in physiology as they show how Ca2+ can be used at a subcellular level, to signal both local changes, known as local control, as well as whole cell changes.

Within the muscle tissue of animals and humans, contraction and relaxation of the muscle cells (myocytes) is a highly regulated and rhythmic process. In cardiomyocytes, or cardiac muscle cells, muscular contraction takes place due to movement at a structure referred to as the diad, sometimes spelled "dyad." The dyad is the connection of transverse- tubules (t-tubules) and the junctional sarcoplasmic reticulum (jSR). Like skeletal muscle contractions, Calcium (Ca2+) ions are required for polarization and depolarization through a voltage-gated calcium channel. The rapid influx of calcium into the cell signals for the cells to contract. When the calcium intake travels through an entire muscle, it will trigger a united muscular contraction. This process is known as excitation-contraction coupling. This contraction pushes blood inside the heart and from the heart to other regions of the body.

The Anrep effect describes the rapid increase in myocardial contractility in response to the sudden rise in afterload, the pressure the heart must work against to eject blood. This adaptive mechanism allows the heart to sustain stroke volume and cardiac output despite increased resistance. It operates through homeometric autoregulation, meaning that contractility adjustments occur independently of preload or heart rate.

Cardiac physiology or heart function is the study of healthy, unimpaired function of the heart: involving blood flow; myocardium structure; the electrical conduction system of the heart; the cardiac cycle and cardiac output and how these interact and depend on one another.

References

  1. ↑ Santana, Luis F.; Cheng, Edward P.; Lederer, W. Jonathan (2010). "How does the shape of the cardiac action potential control calcium signaling and contraction in the heart?". Journal of Molecular and Cellular Cardiology. 49 (6): 901–903. doi:10.1016/j.yjmcc.2010.09.005. ISSN   1095-8584. PMC   3623268 . PMID   20850450.
  2. 1 2 3 Gordan, Richard; Gwathmey, Judith K.; Xie, Lai-Hua (2015-04-26). "Autonomic and endocrine control of cardiovascular function". World Journal of Cardiology. 7 (4): 204–214. doi: 10.4330/wjc.v7.i4.204 . ISSN   1949-8462. PMC   4404375 . PMID   25914789.
  3. ↑ Marks, Andrew R. (2003). "Calcium and the heart: a question of life and death". The Journal of Clinical Investigation. 111 (5): 597–600. doi:10.1172/JCI18067. ISSN   0021-9738. PMC   151912 . PMID   12618512.
  4. ↑ Wong, A. Y.; Fabiato, A.; Bassingthwaighthe, J. B. (1992). "Model of calcium-induced calcium release mechanism in cardiac cells". Bulletin of Mathematical Biology. 54 (1): 95–116. doi:10.1007/BF02458622. ISSN   0092-8240. PMC   4331357 . PMID   25665663.
  5. ↑ Monfredi, Oliver; Dobrzynski, Halina; Mondal, Tapas; Boyett, Mark R.; Morris, Gwilym M. (2010). "The Anatomy and Physiology of the Sinoatrial Node-A Contemporary Review: SINOATRIAL NODAL ANATOMY AND PHYSIOLOGY". Pacing and Clinical Electrophysiology. 33 (11): 1392–1406. doi:10.1111/j.1540-8159.2010.02838.x. PMID   20946278.
  6. ↑ Kurtenbach, Stefan; Kurtenbach, Sarah; Zoidl, Georg (2014). "Gap junction modulation and its implications for heart function". Frontiers in Physiology. 5: 82. doi: 10.3389/fphys.2014.00082 . ISSN   1664-042X. PMC   3936571 . PMID   24578694.
  7. ↑ Hong, TingTing; Shaw, Robin M. (2017). "Cardiac T-Tubule Microanatomy and Function". Physiological Reviews. 97 (1): 227–252. doi:10.1152/physrev.00037.2015. ISSN   0031-9333. PMC   6151489 . PMID   27881552.
  8. ↑ Hinch, R.; Greenstein, J. L.; Tanskanen, A. J.; Xu, L.; Winslow, R. L. (2004). "A simplified local control model of calcium-induced calcium release in cardiac ventricular myocytes". Biophysical Journal. 87 (6): 3723–3736. Bibcode:2004BpJ....87.3723H. doi:10.1529/biophysj.104.049973. ISSN   0006-3495. PMC   1304886 . PMID   15465866.
  9. ↑ Lodish, H.; Berk, A.; Zipursky, L.S; Matsudaira, P.; Baltimore, D.; Darnell, J. (2000). "Muscle: A specialized Contractile machine". Archived from the original on April 27, 2016.
  10. ↑ Balke, C. W.; Egan, T. M.; Wier, W. G. (1994-02-01). "Processes that remove calcium from the cytoplasm during excitation-contraction coupling in intact rat heart cells". The Journal of Physiology. 474 (3): 447–462. doi:10.1113/jphysiol.1994.sp020036. ISSN   0022-3751. PMC   1160336 . PMID   8014906.
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