The extraocular muscles are the six muscles that control movement of the eye and one muscle that controls eyelid elevation. The actions of the six muscles responsible for eye movement depend on the position of the eye at the time of muscle contraction. Since only a small part of the eye called the fovea provides sharp vision, the eye must move to follow a target. Eye movements must be fast; this is seen in scenarios like reading. Although under voluntary control, most eye movement is accomplished without conscious effort. How the integration between voluntary and involuntary control of the eye occurs is a subject of continuing research, it is known, that the vestibulo-ocular reflex plays an important role in the involuntary movement of the eye. Four of the extraocular muscles have their origin in the back of the orbit in a fibrous ring called the annulus of Zinn: the four rectus muscles; the four rectus muscles attach directly to the front half of the eye, are named after their straight paths. Note that medial and lateral are relative terms.
Medial indicates near the midline, lateral describes a position away from the midline. Thus, the medial rectus is the muscle closest to the nose; the superior and inferior recti do not pull straight back on the eye, because both muscles pull medially. This posterior medial angle causes the eye to roll with contraction of either the superior rectus or inferior rectus muscles; the extent of rolling in the recti is less than the oblique, opposite from it. The superior oblique muscle originates at the back of the orbit, getting rounder as it courses forward to a rigid, cartilaginous pulley, called the trochlea, on the upper, nasal wall of the orbit; the muscle becomes tendinous about 10mm before it passes through the pulley, turning across the orbit, inserts on the lateral, posterior part of the globe. Thus, the superior oblique travels posteriorly for the last part of its path, going over the top of the eye. Due to its unique path, the superior oblique, when activated, pulls the eye laterally; the last muscle is the inferior oblique, which originates at the lower front of the nasal orbital wall, passes under the LR to insert on the lateral, posterior part of the globe.
Thus, the inferior oblique pulls the eye laterally. The movements of the extraocular muscles take place under the influence of a system of extraocular muscle pulleys, soft tissue pulleys in the orbit; the extraocular muscle pulley system is fundamental to the movement of the eye muscles, in particular to ensure conformity to Listing's law. Certain diseases of the pulleys cause particular patterns of incomitant strabismus. Defective pulley functions can be improved by surgical interventions; the extraocular muscles are supplied by branches of the ophthalmic artery. This is done either directly or indirectly, as in the lateral rectus muscle, via the lacrimal artery, a main branch of the ophthalmic artery. Additional branches of the ophthalmic artery include the ciliary arteries, which branch into the anterior ciliary arteries; each rectus muscle receives blood from two anterior ciliary arteries, except for the lateral rectus muscle, which receives blood from only one. The exact number and arrangement of these cilary arteries may vary.
Branches of the infraorbital artery supply inferior oblique muscles. The nuclei or bodies of these nerves are found in the brain stem; the nuclei of the abducens and oculomotor nerves are connected. This is important in coordinating the motion of the lateral rectus in one eye and the medial action on the other. In one eye, in two antagonistic muscles, like the lateral and medial recti, contraction of one leads to inhibition of the other. Muscles show small degrees of activity when resting, keeping the muscles taut; this "tonic" activity is brought on by discharges of the motor nerve to the muscle. The extraocular muscles develop along with the fatty tissue of the eye socket. There are three centers of growth that are important in the development of the eye, each is associated with a nerve. Hence the subsequent nerve supply of the eye muscles is from three cranial nerves; the development of the extraocular muscles is dependent on the normal development of the eye socket, while the formation of the ligament is independent.
Below is a table of each of the extraocular muscles and their innervation and insertions, the primary actions of the muscles. Intermediate directions are controlled by simultaneous actions of multiple muscles; when one shifts the gaze horizontally, one eye will move laterally and the other will move medially. This may be neurally coordinated by the central nervous system, to make the eyes move together and involuntarily; this is a key factor in the study of strabismus, the inability of the eyes to be directed to one point. There are two main kinds of movement: disjunctive; the former is typical when shifting gaze right or left, the latter is convergence of the two eyes on a near object. Disjunction can be performed voluntarily, but is triggered by the nearness of the target object. A "see-saw" movement, one eye looking up and the other down, is possible, but not voluntarily. To avoi
Proprioception, is the sense of self-movement and body position. It is sometimes described as the "sixth sense". Proprioception is mediated by mechanically-sensitive proprioceptor neurons distributed throughout an animal's body. Most vertebrates possess three basic types of proprioceptors: muscle spindles, which are embedded in skeletal muscle fibers, Golgi tendon organs, which lie at the interface of muscles and tendons, joint receptors, which are low-threshold mechanoreceptors embedded in joint capsules. Many invertebrates, such as insects possess three basic proprioceptor types with analogous functional properties: chordotonal neurons, campaniform sensilla, hair plates; the central nervous system integrates information from proprioception and other sensory systems, such as vision and the vestibular system, to create an overall representation of body position and acceleration. The sense of proprioception is ubiquitous across mobile animals, is essential for the motor coordination of the body.
More proprioception has been described in flowering land plants. Proprioception is from Latin proprius, meaning "one's own", "individual", capio, capere, to take or grasp, thus to grasp one's own position in space, including the position of the limbs in relation to each other and the body as a whole. The word kinesthesia or kinæsthesia refers to movement sense, but has been used inconsistently to refer either to proprioception alone or to the brain's integration of proprioceptive and vestibular inputs. Kinesthesia is a modern medical term composed of elements from Greek; the position-movement sensation was described in 1557 by Julius Caesar Scaliger as a "sense of locomotion". Much in 1826, Charles Bell expounded the idea of a "muscle sense", credited as one of the first descriptions of physiologic feedback mechanisms. Bell's idea was that commands are carried from the brain to the muscles, that reports on the muscle's condition would be sent in the reverse direction. In 1847 the London neurologist Robert Todd highlighted important differences in the anterolateral and posterior columns of the spinal cord, suggested that the latter were involved in the coordination of movement and balance.
At around the same time, Moritz Heinrich Romberg, a Berlin neurologist, was describing unsteadiness made worse by eye closure or darkness, now known as the eponymous Romberg's sign, once synonymous with tabes dorsalis, that became recognised as common to all proprioceptive disorders of the legs. In 1880, Henry Charlton Bastian suggested "kinaesthesia" instead of "muscle sense" on the basis that some of the afferent information comes from other structures, including tendons and skin. In 1889, Alfred Goldscheider suggested a classification of kinaesthesia into three types: muscle and articular sensitivity. In 1906, Charles Scott Sherrington published a landmark work that introduced the terms "proprioception", "interoception", "exteroception"; the "exteroceptors" are the organs that provide information originating outside the body, such as the eyes, ears and skin. The interoceptors provide information about the internal organs, the "proprioceptors" provide information about movement derived from muscular and articular sources.
Using Sherrington's system and anatomists search for specialised nerve endings that transmit mechanical data on joint capsule and muscle tension, which play a large role in proprioception. Primary endings of muscle spindles "respond to the size of a muscle length change and its speed" and "contribute both to the sense of limb position and movement". Secondary endings of muscle spindles detect changes in muscle length, thus supply information regarding only the sense of position. Muscle spindles are stretch receptors, it has been accepted that cutaneous receptors contribute directly to proprioception by providing "accurate perceptual information about joint position and movement", this knowledge is combined with information from the muscle spindles. A major component of proprioception is joint position sense, determined by measuring the accuracy of joint–angle replication. Clinical aspects of joint position sense are measured in joint position matching tests that measure a subject's ability to detect an externally imposed passive movement, or the ability to reposition a joint to a predetermined position.
These involve an individual's ability to perceive the position of a joint without the aid of vision. It is assumed that the ability of one of these aspects will be related to another; this suggests that while these components may well be related in a cognitive manner, they may in fact be physiologically separate. More recent work into the mechanism of ankle sprains suggests that the role of reflexes may be more limited due to their long latencies, as ankle sprain events occur in 100 ms or less. In accordance, a model has been proposed to include a'feedforward' component of proprioception, whereby the subject will have central information about the body's position before attaining it. Kinesthesia is a key component in muscle memory and hand-eye coordination, training can improve this sense; the ability to swing a golf club or to catch a ball requires a finely tuned sense of the position o
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter. Like other transmembrane receptors, acetylcholine receptors are classified according to their "pharmacology," or according to their relative affinities and sensitivities to different molecules. Although all acetylcholine receptors, by definition, respond to acetylcholine, they respond to other molecules as well. Nicotinic acetylcholine receptors are responsive to nicotine; the nicotine ACh receptor is a Na+, K+ and Ca2+ ion channel. Muscarinic acetylcholine receptors are responsive to muscarine. Nicotinic and muscarinic are two main kinds of "cholinergic" receptors. Molecular biology has shown that the nicotinic and muscarinic receptors belong to distinct protein superfamilies. Nicotinic receptors are of two types: Nn. Nm is located in the neuromuscular junction which causes the contraction of skeletal muscles by way of end-plate potential. Nn causes depolarization in autonomic ganglia resulting in post ganglionic impulse.
Nicotinic receptors cause the release of catecholamine from the adrenal medulla, site specific excitation or inhibition in brain. Both Nm and Nn are Na+ and Ca2+ channel linked but Nn is linked with an extra K+ channel; the nAChRs are ligand-gated ion channels, like other members of the "cys-loop" ligand-gated ion channel superfamily, are composed of five protein subunits symmetrically arranged like staves around a barrel. The subunit composition is variable across different tissues; each subunit contains four regions which span the membrane and consist of 20 amino acids. Region II which sits closest to the pore lumen, forms the pore lining. Binding of acetylcholine to the N termini of each of the two alpha subunits results in the 15° rotation of all M2 helices; the cytoplasm side of the nAChR receptor has rings of high negative charge that determine the specific cation specificity of the receptor and remove the hydration shell formed by ions in aqueous solution. In the intermediate region of the receptor, within the pore lumen and leucine residues define a hydrophobic region through which the dehydrated ion must pass.
The nAChR is found at the edges of junctional folds at the neuromuscular junction on the postsynaptic side. The diffusion of Na+ and K+ across the receptor causes depolarization, the end-plate potential, that opens voltage-gated sodium channels, which allows for firing of the action potential and muscular contraction. In contrast, the mAChRs are not ion channels, but belong instead to the superfamily of G-protein-coupled receptors that activate other ionic channels via a second messenger cascade; the muscarine cholinergic receptor activates a G-protein. The alpha subunit of the G-protein activates guanylate cyclase while the beta-gamma subunit activates the K-channels and therefore hyperpolarize the cell; this causes a decrease in cardiac activity. Nicotinic acetylcholine receptors can be blocked by curare and toxins present in the venoms of snakes and shellfishes, like α-bungarotoxin. Drugs such as the neuromuscular blocking agents bind reversibly to the nicotinic receptors in the neuromuscular junction and are used in anaesthesia.
Nicotinic receptors are the primary mediator of the effects of nicotine. In myasthenia gravis, the receptor at the neuromuscular junction is targeted by antibodies, leading to muscle weakness. Muscarinic acetylcholine receptors can be blocked by the drugs scopolamine. Congenital myasthenic syndrome is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. Postsynaptic defects are the most frequent cause of CMS and result in abnormalities in nicotinic acetylcholine receptors; the majority of mutations causing CMS are found in the AChR subunits genes. Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult acetylcholine receptor subunits. Mutations of the AChR result in endplate deficiency. Most of the mutations of the AChR are mutations of the CHRNE gene; the CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency.
CHRNE is associated with changing the kinetic properties of the AChR. One type of mutation of the epsilon subunit of the AChR introduces an Arg into the binding site at the α/ε subunit interface of the receptor; the addition of a cationic Arg into the anionic environment of the AChR binding site reduces the kinetic properties of the receptor. The result of the newly introduced ARG is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, an weakened channel opening probability; this type of mutation results in an fatal form of CMS. Muscarinic acetylcholine receptor M5 Nicotinic agonists Acetylcholine receptor: PMAP The Proteolysis Map-animation Acetylcholine+Receptors at the US National Library of Medicine Medical Subject Headings Acetlycholine Receptor: Molecule of The Month by David Goodsell Acetylcholine receptors: muscarinic and nicotinic by Flavio Guzman ANS receptors-overview
In physiology, an action potential occurs when the membrane potential of a specific axon location rises and falls: this depolarisation causes adjacent locations to depolarise. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, endocrine cells, in some plant cells. In neurons, action potentials play a central role in cell-to-cell communication by providing for—or with regard to saltatory conduction, assisting—the propagation of signals along the neuron's axon toward synaptic boutons situated at the ends of an axon. In other types of cells, their main function is to activate intracellular processes. In muscle cells, for example, an action potential is the first step in the chain of events leading to contraction. In beta cells of the pancreas, they provoke release of insulin. Action potentials in neurons are known as "nerve impulses" or "spikes", the temporal sequence of action potentials generated by a neuron is called its "spike train".
A neuron that emits an action potential, or nerve impulse, is said to "fire". Action potentials are generated by special types of voltage-gated ion channels embedded in a cell's plasma membrane; these channels are shut when the membrane potential is near the resting potential of the cell, but they begin to open if the membrane potential increases to a defined threshold voltage, depolarising the transmembrane potential. When the channels open, they allow an inward flow of sodium ions, which changes the electrochemical gradient, which in turn produces a further rise in the membrane potential; this causes more channels to open, producing a greater electric current across the cell membrane and so on. The process proceeds explosively until all of the available ion channels are open, resulting in a large upswing in the membrane potential; the rapid influx of sodium ions causes the polarity of the plasma membrane to reverse, the ion channels rapidly inactivate. As the sodium channels close, sodium ions can no longer enter the neuron, they are actively transported back out of the plasma membrane.
Potassium channels are activated, there is an outward current of potassium ions, returning the electrochemical gradient to the resting state. After an action potential has occurred, there is a transient negative shift, called the afterhyperpolarization. In animal cells, there are two primary types of action potentials. One type is generated by the other by voltage-gated calcium channels. Sodium-based action potentials last for under one millisecond, but calcium-based action potentials may last for 100 milliseconds or longer. In some types of neurons, slow calcium spikes provide the driving force for a long burst of emitted sodium spikes. In cardiac muscle cells, on the other hand, an initial fast sodium spike provides a "primer" to provoke the rapid onset of a calcium spike, which produces muscle contraction. In the Hodgkin–Huxley membrane capacitance model, the speed of transmission of an action potential was undefined and it was assumed that adjacent areas became depolarised due to released ion interference with neighbouring channels.
Measurements of ion diffusion and radii have since shown this not to be possible. Moreover, contradictory measurements of entropy changes and timing disputed the capacitance model as acting alone. Nearly all cell membranes in animals and fungi maintain a voltage difference between the exterior and interior of the cell, called the membrane potential. A typical voltage across an animal cell membrane is −70 mV; this means that the interior of the cell has a negative voltage of one-fifteenth of a volt relative to the exterior. In most types of cells, the membrane potential stays constant; some types of cells, are electrically active in the sense that their voltages fluctuate over time. In some types of electrically active cells, including neurons and muscle cells, the voltage fluctuations take the form of a rapid upward spike followed by a rapid fall; these up-and-down cycles are known as action potentials. In some types of neurons, the entire up-and-down cycle takes place in a few thousandths of a second.
In muscle cells, a typical action potential lasts about a fifth of a second. In some other types of cells, in plants, an action potential may last three seconds or more; the electrical properties of a cell are determined by the structure of the membrane that surrounds it. A cell membrane consists of a lipid bilayer of molecules in which larger protein molecules are embedded; the lipid bilayer is resistant to movement of electrically charged ions, so it functions as an insulator. The large membrane-embedded proteins, in contrast, provide channels through which ions can pass across the membrane. Action potentials are driven by channel proteins whose configuration switches between closed and open states as a function of the voltage difference between the interior and exterior of the cell; these voltage-sensitive proteins are known as voltage-gated ion channels. All cells in animal body tissues are electrically polarized – in other words, they maintain a voltage difference across the cell's plasma membrane, known as the membrane potential.
This electrical polarization results from a complex interplay between protein structures embedded in the membrane called ion pumps and ion channels. In neurons, the types of ion channels in the membrane vary across different parts of the cell, giving the dendrites and cell body different electrical properties; as a result, some parts of the membrane of a neuron may be excitable (capable of generating action potentia
Calcium channel blocker
Calcium channel blockers, calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e. as medications to decrease blood pressure in patients with hypertension. CCBs are effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, to reduce chest pain caused by angina pectoris. N-type, L-type, T-type voltage-dependent calcium channels are present in the zona glomerulosa of the human adrenal gland, CCBs can directly influence the biosynthesis of aldosterone in adrenocortical cells, with consequent impact on the clinical treatment of hypertension with these agents. CCBs have been shown to be more effective than beta blockers at lowering cardiovascular mortality, but they are associated with more side effects.
Potential major risks however were found to be associated with short-acting CCBs. Dihydropyridine calcium channel blockers are derived from the molecule dihydropyridine and used to reduce systemic vascular resistance and arterial pressure. Sometimes when they are used to treat angina, the vasodilation and hypotension can lead to reflex tachycardia, which can be detrimental for patients with ischemic symptoms because of the resulting increase in myocardial oxygen demand. Dihydropyridine calcium channel blockers can worsen proteinuria in patients with nephropathy; this CCB class is identified by the suffix "-dipine". Amlodipine Aranidipine Azelnidipine Barnidipine Benidipine Cilnidipine Not available in US Clevidipine Efonidipine Felodipine Isradipine Lacidipine Lercanidipine Manidipine Nicardipine Nifedipine Nilvadipine Nimodipine This substance can pass the blood-brain barrier and is used to prevent cerebral vasospasm. Nisoldipine Nitrendipine Pranidipine Phenylalkylamine calcium channel blockers are selective for myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm, are used to treat angina.
They have minimal vasodilatory effects compared with dihydropyridines and therefore cause less reflex tachycardia, making it appealing for treatment of angina, where tachycardia can be the most significant contributor to the heart's need for oxygen. Therefore, as vasodilation is minimal with the phenylalkylamines, the major mechanism of action is causing negative inotropy. Phenylalkylamines are thought to access calcium channels from the intracellular side, although the evidence is somewhat mixed. Fendiline Gallopamil Verapamil Benzothiazepine calcium channel blockers belong to the benzothiazepine class of compounds and are an intermediate class between phenylalkylamine and dihydropyridines in their selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines. Diltiazem While most of the agents listed above are selective, there are additional agents that are considered nonselective.
These include mibefradil, flunarizine and fendiline. Gabapentinoids, such as gabapentin and pregabalin, are selective blockers of α2δ subunit-containing voltage-gated calcium channels, they are used to treat epilepsy and neuropathic pain. Ziconotide, a peptide compound derived from the omega-conotoxin, is a selective N-type calcium channel blocker that has potent analgesic properties that are equivalent to approximate 1,000 times that of morphine, it must be delivered via the intrathecal route via an intrathecal infusion pump. Side effects of these drugs may include but are not limited to: Constipation Dizziness, redness in the face Fluid buildup in the legs and ankle edema Gingival overgrowth Rapid heart rate Slow heart rate Research indicates ethanol is involved in the inhibition of L-type calcium channels. One study showed the nature of ethanol binding to L-type calcium channels is according to first-order kinetics with a Hill coefficient around 1; this indicates ethanol binds independently to the channel.
Early studies showed a link between calcium and the release of vasopressin by the secondary messenger system. Vasopressin levels are reduced after the ingestion of alcohol; the lower levels of vasopressin from the consumption of alcohol have been linked to ethanol acting as an antagonist to voltage-gated calcium channels. Studies conducted by Treistman et al. in the aplysia confirm inhibition of VGCC by ethanol. Voltage clamp recordings have been done on the aplysia neuron. VGCCs were isolated and calcium current was recorded using patch clamp technique having ethanol as a treatment. Recordings were replicated at varying concentrations at a voltage clamp of +30 mV. Results showed. Similar results have shown to be true in single-channel recordings from isolated nerve terminal of rats that ethanol does in fact block VGCCs. Studies done by Katsura et al. in 2006 on mouse cerebral cortical neurons, show the effects of prolonged ethanol
Levator palpebrae superioris muscle
The levator palpebrae superioris is the muscle in the orbit that elevates the superior eyelid. The levator palpebrae superioris originates on the lesser wing of the sphenoid bone, just above the optic foramen, it decreases in thickness and becomes the levator aponeurosis. This portion inserts on the skin of the upper eyelid, as well as the superior tarsal plate, it is a skeletal muscle. The superior tarsal muscle, a smooth muscle, is attached to the levator palpebrae superioris, inserts on the superior tarsal plate as well; as with most of the muscles of the orbit, the levator palpebrae receives somatic motor input from the ipsilateral superior division of the oculomotor nerve. An adjoining smooth muscle, the superior tarsal muscle, confused to be a portion of the levator palpebrae superioris, is only attached, it is separately innervated by sympathetic fibers that originate in the cervical spinal cord; the levator palpebrae superioris muscle retracts the upper eyelid. Damage to this muscle or its innervation can cause ptosis, drooping of the eyelid.
Lesions in CN III can cause ptosis, because without stimulation from the oculomotor nerve the levator palpebrae cannot oppose the force of gravity, the eyelid droops. Ptosis can result from damage to the adjoining superior tarsal muscle or its sympathetic innervation; such damage to the sympathetic supply presents as a partial ptosis. It is important to distinguish between these two different causes of ptosis; this can be done clinically without issue, as each type of ptosis is accompanied by other distinct clinical findings. Blepharospasm Ptosis Superior tarsal muscle Anatomy figure: 29:01-01 at Human Anatomy Online, SUNY Downstate Medical Center lesson3 at The Anatomy Lesson by Wesley Norman
A neuromuscular junction is a chemical synapse formed by the contact between a motor neuron and a muscle fiber. It is at the neuromuscular junction that a motor neuron is able to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to function—and just to maintain muscle tone, avoiding atrophy. Synaptic transmission at the neuromuscular junction begins when an action potential reaches the presynaptic terminal of a motor neuron, which activates voltage-dependent calcium channels to allow calcium ions to enter the neuron. Calcium ions bind to sensor proteins on synaptic vesicles, triggering vesicle fusion with the cell membrane and subsequent neurotransmitter release from the motor neuron into the synaptic cleft. In vertebrates, motor neurons release acetylcholine, a small molecule neurotransmitter, which diffuses across the synaptic cleft and binds to nicotinic acetylcholine receptors on the cell membrane of the muscle fiber known as the sarcolemma. NAChRs are ionotropic receptors.
The binding of ACh to the receptor can depolarize the muscle fiber, causing a cascade that results in muscle contraction. Neuromuscular junction diseases can be of autoimmune origin. Genetic disorders, such as Duchenne muscular dystrophy, can arise from mutated structural proteins that comprise the neuromuscular junction, whereas autoimmune diseases, such as myasthenia gravis, occur when antibodies are produced against nicotinic acetylcholine receptors on the sarcolemma. At the neuromuscular junction presynaptic motor axons terminate 30 nanometers from the cell membrane or sarcolemma of a muscle fiber; the sarcolemma at the junction has invaginations called postjunctional folds, which increase its surface area facing the synaptic cleft. These postjunctional folds form the motor endplate, studded with nicotinic acetylcholine receptors at a density of 10,000 receptors/micrometer2; the presynaptic axons terminate in bulges called terminal boutons that project toward the postjunctional folds of the sarcolemma.
In the frog each motor nerve terminal contains about 300,000 vesicles, with an average diameter of 0.05 micrometers. The vesicles contain acetylcholine; some of these vesicles are gathered into groups of fifty, positioned at active zones close to the nerve membrane. Active zones are about 1 micrometer apart; the 30 nanometer cleft between nerve ending and endplate contains a meshwork of acetylcholinesterase at a density of 2,600 enzyme molecules/micrometer2, held in place by the structural proteins dystrophin and rapsyn. Present is the receptor tyrosine kinase protein MuSK, a signaling protein involved in the development of the neuromuscular junction, held in place by rapsyn. About once every second in a resting junction randomly one of the synaptic vesicles fuses with the presynaptic neuron's cell membrane in a process mediated by SNARE proteins. Fusion results in the emptying of the vesicle's contents of 7000-10,000 acetylcholine molecules into the synaptic cleft, a process known as exocytosis.
Exocytosis releases acetylcholine in packets that are called quanta. The acetylcholine quantum diffuses through the acetylcholinesterase meshwork, where the high local transmitter concentration occupies all of the binding sites on the enzyme in its path; the acetylcholine that reaches the endplate activates ~2,000 acetylcholine receptors, opening their ion channels which permits sodium ions to move into the endplate producing a depolarization of ~0.5 mV known as a miniature endplate potential. By the time the acetylcholine is released from the receptors the acetylcholinesterase has destroyed its bound ACh, which takes about ~0.16 ms, hence is available to destroy the ACh released from the receptors. When the motor nerve is stimulated there is a delay of only 0.5 to 0.8 msec between the arrival of the nerve impulse in the motor nerve terminals and the first response of the endplate The arrival of the motor nerve action potential at the presynaptic neuron terminal opens voltage-dependent calcium channels and Ca2+ ions flow from the extracellular fluid into the presynaptic neuron's cytosol.
This influx of Ca2+ causes several hundred neurotransmitter-containing vesicles to fuse with the presynaptic neuron's cell membrane through SNARE proteins to release their acetylcholine quanta by exocytosis. The endplate depolarization by the released acetylcholine is called an endplate potential; the EPP is accomplished when ACh binds the nicotinic acetylcholine receptors at the motor end plate, causes an influx of sodium ions. This influx of sodium ions generates the EPP, triggers an action potential which travels along the sarcolemma and into the muscle fiber via the transverse tubules by means of voltage-gated sodium channels; the conduction of action potentials along the transverse tubules stimulates the opening of voltage-gated Ca2+ channels which are mechanically coupled to Ca2+ release channels in the sarcoplasmic reticulum. The Ca2+ diffuses out of the sarcoplasmic reticulum to the myofibrils so it can stimulate contraction; the endplate potential is thus responsible for setting up an action potential in the muscle fiber which triggers muscle contraction.
The transmission from nerve to muscle is so rapid because each quantum of acetylcholine reaches the endplate in millimolar concentrations, high enough to combine with a receptor with a low affinity, which swiftly releases the bound transmitter. Acetylcholine is a neurotransmitter synthesized from dietary choline and acetyl-CoA, is involved in the stimulation of muscle tissue in vertebrates as well as i