Excitation-contraction coupling
Encyclopedia
Excitation-contraction coupling is a term coined in 1952 to describe the physiological process of converting an electrical stimulus to a mechanical response . This process is fundamental to muscle physiology, whereby the electrical stimulus is usually an action potential and the mechanical response is contraction. EC coupling can be dysregulated in many disease conditions.
Though EC coupling has been known for over half a century, it is still an active area of biomedical research. The general scheme is that an action potential arrives to depolarize the cell membrane. By mechanisms specific to the muscle type, this depolarization results in an increase in cytosolic calcium
that is called a calcium transient. This increase in calcium activates calcium-sensitive contractile proteins that then use ATP
to cause cell shortening.
, which involves the conduction of calcium ions into the cell triggering further release of ions into the cytoplasm (about 75% of calcium present in the cytoplasm during contraction is release from the sarcoplasmic reticulum).
Some stimuli for smooth muscle contraction, however, are neural. All neural input is autonomic (involuntary). In these the mechanism of excitation-contraction coupling is as follows: parasympathetic input uses the neurotransmitter acetylcholine. Acetylcholine receptors on smooth muscle are of the muscarinic receptor type; as such they are metabotropic, or G-protein / second messenger coupled. Sympathetic input uses different neurotransmitters; the primary one is norepinephrine. All adrenergic receptors are also metabotropic. The exact effects on the smooth muscle depend on the specific characteristics of the receptor activated--both parasympathetic input and sympathetic input can be either excitatory (contractile) or inhibitory (relaxing). The main mechanism for actual coupling involves varying the calcium-sensitivity of specific cellular machinery. However it occurs, increased intracellular calcium binds calmodulin, which activates myosin light chain kinase (MLCK). MLCK phosphorylates the regulatory light chains of the myosin heads. Phosphorylated myosin heads are able to cross bridge-cycle. Thus, the degree to and velocity of which a whole smooth muscle contracts depends on the level of phosphorylation of myosin heads. Myosin light chain phosphatase removes the phosphate groups from the myosin heads, thus ending cycling (and leaving the muscle in latch-state).
Though EC coupling has been known for over half a century, it is still an active area of biomedical research. The general scheme is that an action potential arrives to depolarize the cell membrane. By mechanisms specific to the muscle type, this depolarization results in an increase in cytosolic calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
that is called a calcium transient. This increase in calcium activates calcium-sensitive contractile proteins that then use ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
to cause cell shortening.
Skeletal muscle
In skeletal muscle the method of excitation contraction coupling relies on the ryanodine receptor being activated by a domain spanning the space between the T tubules and the sarcoplasmic reticulum to produce the calcium transient responsible for allowing contraction.- The alpha motor neuronAlpha motor neuronAlpha motor neurons are large lower motor neurons of the brainstem and spinal cord. They innervate extrafusal muscle fibers of skeletal muscle and are directly responsible for initiating their contraction...
produces an action potentialAction potentialIn physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
that propagates down its axon to the neuromuscular junctionNeuromuscular junctionA neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
. - The action potential is sensed by a voltage-dependent calcium channelVoltage-dependent calcium channelVoltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+...
which causes an influx of Ca2+ ions. This influx results in exocytosisExocytosisExocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
of synaptic vesicleSynaptic vesicleIn a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
s containing acetylcholineAcetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
. - Acetylcholine diffuses across the synapseSynapseIn the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
and binds to nicotinic acetylcholine receptorNicotinic acetylcholine receptorNicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
s on the myocyte, opening them. An influx of Na+ and an efflux of K+ results, depolarizing the cell and generating an end-plate potentialEnd-plate potentialEnd plate potentials are the depolarizations of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance...
. - The end-plate potential propagates throughout the myocyte's sarcolemma and into the T-tubuleT-tubuleA T-tubule is a deep invagination of the sarcolemma, which is the plasma membrane, only found in skeletal and cardiac muscle cells...
system. - The T-tubule system contains voltage-dependent calcium channelVoltage-dependent calcium channelVoltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+...
s known as dihydropyridine receptors (DHP) which are activated by the end-plate potential. - Rather than releasing calcium from the T-tubules, activated dihydropyridine receptors transmit the voltage-mediated signal through a mechanical linkage to the ryanodine receptorRyanodine receptorRyanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
s in the sarcoplasmic reticulum. This process involves a conformational change which allosterically activates type 1 ryanodine receptorsRYR1Ryanodine receptor 1 also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is a protein primarily found in skeletal muscle...
. - Activated ryanodine receptors then open their channels.
- Opening of the ryanodine receptors allows a flow of Ca2+ from the sarcoplasmic reticulum into the cytoplasm. In this release, Ca2+ unbinds from the calcium-binding proteinCalcium-binding proteinCalcium-binding proteins are proteins that participate in calcium cell signalling pathways by binding to Ca2+.The most ubiquitous Ca2+-sensing protein, found in all eukaryotic organisms including yeasts, is calmodulin....
called calsequestrinCalsequestrinCalsequestrin is a calcium-binding protein of the sarcoplasmic reticulum. The protein helps hold calcium in the cisterna of the sarcoplasmic reticulum after a muscle contraction, even though the concentration of calcium in the sarcoplasmic reticulum is much higher than in the cytosol. It also...
. - Ca2+ released from the sarcoplasmic reticulum binds to Troponin CTroponin CTroponin C is a part of the troponin complex. It contains four calcium-binding EF hands. It is a component of thin filaments . It contains an N lobe and a C lobe. The C lobe serves a structural purpose and binds to the N domain of TnI. The C lobe can bind either Ca2+ or Mg2+...
by the actin filaments, which subsequently causes the troponin complexTroponin complexTroponin complex is a heteromeric protein playing an important role in the regulation of skeletal and cardiac muscle contraction. Troponin complex consists of three different subunits – troponin T , troponin I and troponin C . Each subunit is responsible for a part of troponin complex function...
to pull tropomyosin away from the myosin binding sites on nearby actin filaments. Myosin cross-bridge binding sites on the actin filaments are now uncovered. - By hydrolyzing ATP, myosinMyosinMyosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...
forms cross bridges with the actin filaments. Activation of this cross-bridge cycling may induce a shortening of the sarcomeres and the muscle as a whole, but not if the tension is insufficient to overcome the load imparted on the muscle. - Provided a force is applied that exceedes the load, a concentric contraction initiates. During this contraction, actin's interaction with myosin results in its movement toward the center of the sarcomereSarcomereA sarcomere is the basic unit of a muscle. Muscles are composed of tubular muscle cells . Muscle cells are composed of tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as dark and light bands...
, or M-line, through a series of calcium-induced power strokes. - A sarcomere will remain contracted in this tightly bound state of rigor mortisRigor mortisRigor mortis is one of the recognizable signs of death that is caused by a chemical change in the muscles after death, causing the limbs of the corpse to become stiff and difficult to move or manipulate...
unless sufficient ATP is present to bind with myosin, as a myosin head that is not bound to actin is bound to ATP. - Simultaneously, the sarco/endoplasmic reticulum Ca2+-ATPaseSERCASERCA, or sarco/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase.-Function:SERCA resides in the sarcoplasmic reticulum within muscle cells...
actively pumps Ca2+ back into the sarcoplasmic reticulum where Ca2+ rebinds to calsequestrin. - With Ca2+ no longer bound to troponin C, the troponin complex slips position from the open state to its blocking position. As a consequence of this change, tropomyosin slips into a position that covers the binding sites on actin.
- Since cross-bridge cycling is ceasing then any load on the muscle causes the inactive sarcomeres to lengthen.
Cardiac muscle
In cardiac muscle, the method is dependent on a phenomenon called calcium-induced calcium releaseCalcium-induced calcium release
Calcium-induced calcium release is a process whereby calcium can trigger release of further calcium from the muscle sarcoplasmic reticulum. Originally proposed for skeletal muscle in the 1970s, subsequent research has revealed that it is even more pronounced in the cardiac muscle...
, which involves the conduction of calcium ions into the cell triggering further release of ions into the cytoplasm (about 75% of calcium present in the cytoplasm during contraction is release from the sarcoplasmic reticulum).
- An action potential is induced by pacemaker (conduction pathway) cells in the Sinoatrial nodeSinoatrial nodeThe sinoatrial node is the impulse-generating tissue located in the right atrium of the heart, and thus the generator of normal sinus rhythm. It is a group of cells positioned on the wall of the right atrium, near the entrance of the superior vena cava...
or Atrioventricular nodeAtrioventricular nodeThe atrioventricular node is a part of the electrical control system of the heart that coordinates heart rate. It electrically connects atrial and ventricular chambers...
and conducted from non-contractile cardiac myocytes to contractile cells through gap junctions. - The action potential travels along T-tubules among Z-discs and triggers L-type calcium channelL-type calcium channelThe L-type calcium channel is a type of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties....
s (DHP) during the plateau phase of the cardiac action potential, causing a net flux of calcium ions into the cardiac myocyte. - The increase in intracellular calcium ions is detected by ryanodine receptorRyanodine receptorRyanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
s in the membrane of the sarcoplasmic reticulum which transport calcium out into the cytosol in a positive feedbackPositive feedbackPositive feedback is a process in which the effects of a small disturbance on a system include an increase in the magnitude of the perturbation. That is, A produces more of B which in turn produces more of A. In contrast, a system that responds to a perturbation in a way that reduces its effect is...
physiological response. - The cytoplasmic calcium binds to Troponin C, moving the troponin complex off the actin binding site allowing the myosin head to bind to the actin filament.
- Using ATP hydrolysis the myosin head pulls the actin filament to the centre of the sarcomere.
- Intracellular calcium is taken up by the sarco/endoplasmic reticulum ATPaseSERCASERCA, or sarco/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase.-Function:SERCA resides in the sarcoplasmic reticulum within muscle cells...
pump into the sarcoplasm, or ejected from the cell by the sodium-calcium exchangerSodium-calcium exchangerThe sodium-calcium exchanger is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium by allowing Na+ to flow down its gradient across the plasma membrane in exchange for the countertransport of calcium ions...
or the plasma membrane calcium ATPaseCalcium ATPaseCalcium ATPase is a form of P-ATPase that transfers calcium after a muscle has contracted. The calcium ATPase are:*Plasma membrane Ca2+ ATPase *Sarcoplasmic reticulum Ca2+ ATPase - Plasma membrane Ca2+ ATPase :...
. - Intracellular calcium concentration drops and troponin complex returns over the active site of the actin filament, ending contraction.
Smooth muscle
It is important to note that contraction of smooth muscle need not require neural input--that is, it can function without an action potential. It does so by integrating a huge number of other stimuli such as humoral/paracrine (e.g. Epinephrine, Angiotensin II, AVP, Endothelin), metabolic (e.g. oxygen, carbon dioxide, adenosine, potassium ions, hydrogen ions), or physical stimuli (e.g. stretch receptors, shear stress). This integrative character of smooth muscle allows it to function in the tissues in which it exists, such as being the controller of local blood flow to tissues undergoing metabolic changes. In these excitation-free contractions, then, there of course is no excitation-contraction coupling.Some stimuli for smooth muscle contraction, however, are neural. All neural input is autonomic (involuntary). In these the mechanism of excitation-contraction coupling is as follows: parasympathetic input uses the neurotransmitter acetylcholine. Acetylcholine receptors on smooth muscle are of the muscarinic receptor type; as such they are metabotropic, or G-protein / second messenger coupled. Sympathetic input uses different neurotransmitters; the primary one is norepinephrine. All adrenergic receptors are also metabotropic. The exact effects on the smooth muscle depend on the specific characteristics of the receptor activated--both parasympathetic input and sympathetic input can be either excitatory (contractile) or inhibitory (relaxing). The main mechanism for actual coupling involves varying the calcium-sensitivity of specific cellular machinery. However it occurs, increased intracellular calcium binds calmodulin, which activates myosin light chain kinase (MLCK). MLCK phosphorylates the regulatory light chains of the myosin heads. Phosphorylated myosin heads are able to cross bridge-cycle. Thus, the degree to and velocity of which a whole smooth muscle contracts depends on the level of phosphorylation of myosin heads. Myosin light chain phosphatase removes the phosphate groups from the myosin heads, thus ending cycling (and leaving the muscle in latch-state).