2011 Group 6 Project
- 1 Neuromuscular Junctions
- 2 Introduction
- 3 History
- 4 Mechanism of action
- 5 Important Structural Components
- 6 Development of the neuromuscular junction
- 7 Common neuromuscular junction disorders
- 8 Current associated research
- 9 Future research
- 10 External links
- 11 Glossary
- 12 References
A Neuromuscular junction (NMJ) is a connection between an axon of a motor neuron and the motor end plates on a muscle fibre. The NMJ can be found in both smooth and skeletal muscle fibres, with different purpose and mechanisms which may involve different receptors. Starting with historic researches, this group project establishes detailed information on how this junction works, which may lead to a skeletal muscle contraction, followed by a description for each of its engines involved during this process. Additionally, the NMJ is the site of some well-known diseases which will be briefly described in a table of NMJ’s disorders. Currently, the NMJ is a research topic in many areas such as pharmacology, pathology, physiology and medicine.
Historic researchers in NMJ:
In 1672, Myasthenia gravis (MG) was first described by Thomas Willis. It is an acquired autoimmune disease with antibodies against the nicotinic acetylcholine receptor (AChR) at the NMJ. 
In 1842, Claude Bernard concluded that the arrow poison curare acts at the NMJ to interrupt the stimulation of muscle by nerve impulses. 
In 1850, Claude Bernard demonstrated that the observed paralysis was mediated via the NMJ, although the precise mechanism was at that time unknown. 
In 1914, Sir Henry Dale, (in 1936, he was warded the Nobel Prize for Medicine and Physiology), investigating the pharmacological properties of ACh, distinguished two actions that were reproduced by the alkaloids, muscarine and nicotine. As the effects of muscarine mimicked the parasympathetic nervous system, he termed the receptors muscarinic, whereas those in autonomic ganglia and at the skeletal NMJ were termed nicotinic. 
In 1952 - 1954, the name end-plate potential is used since Fatt&Katz (1952) and Del Castillo & Katz (1954) studied the endplate potential (epp) at NMJ. They concluded that the ACh molecules were released in packets containing several thousand ACh molecules revealing the quantal nature of synaptic transmission. 
Mechanism of action
The mechanism of action of NMJ involves many steps and engines which harmonically follow each other in which the ability of a muscle to contract or relax depend on. These steps are:
- Nerve impulse reaches the motor nerve terminal
- Specialized proteins forming ion channels in its cell membrane open quickly
- Calcium enters into the axon terminal
- Synaptic vesicles are filled with ACh
- Ca causes some of the vesicle membranes to fuse with the nerve terminal membrane
- ACh content is released into synaptic cleft
- ACh diffuses rapidly across the gap and binds to the ACh receptors (AChRs)
- When this binding occur, small positively charged sodium (Na) ions enter the muscle
- This lead to the depolarization across membrane
- End-plate potential in turn opens the voltage-sensitive Na channels at the synaptic fold
- An “all or nothing” action potential starts which propagates along the muscle fibre in each direction
- Initiation of a muscle contraction occur
- Then, the AChR pore closes
- ACh unbinds and broken down
To understand where this happens and the steps involved, please watch this video
- Efferent neurons
- Originate in the ventral horn of the spinal cord
- Synapse with muscle fibres
- Carry information from the central nervous system to muscles
- Facilitate muscle contraction
- Somatic once are directly involved in the contraction of skeletal muscles
- Influenced by input descending from the brain
- Affected by a class of diseases known as motor neuron diseases
- Amyotrophic lateral sclerosis is characterized by loss of lower neurons in spinal cord and brain stem and upper motor neurons that project in corticospinal tracts. Skeletal muscles innervated by the degenerated lower motor neurons show neurogenic atrophy.
- Cholinergic neurons
- Skeletal muscle movement
- Regulation of smooth muscle
- One of the principle neurotransmitters of the peripheral nervous system
- Released by a motor neuron at the NMJ
- Bind and activate a receptor protein
- A very effective deliverer of sodium ions, which stimulate muscle contractions and excites nerves
- The enzyme acetycholinesterase (AChE) hydrolyzes acetylcholine into acetic acid and choline
- Choline travels back to be recycled into acetylcholine and start the process over again
- Concentration of ACh remains higher if the AChE is inhibited
- AChE inhibitors delay the degradation of acetylcholine
- This inhibitors are used to reverse muscle relaxants and sometimes to treat Alzheimer's disease
Acetylcholine Receptors (AChR's)
Nicotinic and Muscarinic receptors are receptors for acetylcholine. The important difference between the two is their mode of action
- Nicotinic receptors (nAChRs)
-Controls skeletal muscle contraction 
-located at synapses between two neurons and at synapses between neurons and skeletal muscle cells
- Muscarinic receptors (mAChRs)
-Controls smooth muscle contraction
-Metabotropic receptors (G-protein coupled receptors)
-located at the synapses of nerves with smooth or cardiac muscle
-Trigger a chain of chemical events referred to as signal transduction
-Excitation and inhibition response
-Response of mAChRs is slower
For more information on nAChRs and mAChRs see: Nicotinic and Muscarinic Acetylcholine Receptors
Motor End Plate
- Specialised region of the sarcolemma
- Highly folded
- Holds a high concentration of AChRs
- Also called Myoneural Junction 
- Receive neurotransmitters in order to propagate an Action Potential
- Responsible for the terminal tree like branching of a motor axon on a muscle fibre
- Maintains muscle tone through stretch reflex
Important Structural Components
Cellular organization of skeletal muscle:
The NMJ innervates muscle to contract, the following points outline the components of skeletal muscle:
- Epimysium, an external sheath of dense connective tissue surrounds the entire skeletal muscle
- Muscle fibers are arranged in regular bundles
- The connective tissue, perimysium surrounds each bundle
- Each fiber is surround by a delicate connective tissue called endomysium which is mainly composed of basal lamina and reticular fibers
- Characterized by the presence of several nuclei
- These nuclei are located below the sarcolema
- Contain a semifluid cytoplasm called sarcoplasm
- Sarcoplasm is filled with mitochondria and myofibrils
- Filaments (thin and thick) lie parallel to the long axis of the myofibrils
- Sarcoplasmic reticulum ( SR- a saclike membranous network) surrounds each of the myofibrils
- SR is associated with transverse tubules ( T tubules) which are connected with the sarcolema
- T tubules help to transmit signals from the sarcolemma to the myofibrils
Proteins of muscle filaments:
- long filamentous polymers
- consists of two strands of globular monumers
- diameter 5.6nm
- twisted around each other
- double helical formation
- each monomer contain a binding site for myosin
- large complex
- dissociated into two identical heavy chains and two pairs of light chain
- heavy chains are thin, rod-like molecules which are twisted together
- the heads of heavy chains have ATP-binding sites, ATPase activity and the ability to bind to actin
- the light chains are associated with the head
- Troponin (Tn)
- Tn complex bind to tropomyosin’s surface
- complex of three subunits
1. TnT attaches to tropomyosin
2. TnC binds Ca ions
3. TnI inhibits the actin-myosin interaction
- Tropomyosin (Tm)
- long thin molecule
- contains two polypeptide chains
- Tm molecules are bound head to tail
- forming a polymer that run over the actin subunits
- binds to actin and acts as a molecular barrier
- blocks myosin-binding sites in relaxed muscle
- thus, prevents the crossbridge cycle from occurring
- myosin-binding sites are exposed when Ca ions are released
- several Tm’s isoforms
Development of the neuromuscular junction
During week 9, i.e. the beginning of the fetal period, the first neuromuscular junctions appear on the newly created myotubes (muscle fibers form from the fusion of myoblasts into multi-nucleated fibers).
The development of NMJ requires reciprocal signals from nerve and muscle. It can be divided into the following stages:
- Formation of clusters of acetylcholine (ACh) concentrated in the central regions of the myofibers. This is induced by kinase releasing activity of the muscle specific MuSK protein.
- ACh released by branching nerve endings regulates and refines the localization and stabilization of nerve-muscle contact sites.
- Synaptic contacts are stabilized by agrin released from the branching nerve. Agrin enhances the MuSK activity and ACh accumulation.
- Motor axons branch onto specific regions (endplates) of individual muscle fibers.
Common neuromuscular junction disorders
Neuromuscular junction disorders are due to impaired transmission of impulses at the neuromuscular junction. This may result from disorders that affect receptor function, pre- or postsynaptic membrane function, or acetylcholinesterase activity. The majority of diseases in this category are associated with autoimmune, toxic, or inherited conditions.
Current associated research
Current research has shown that the use of embryonic stem cells to replace damaged tissue can be beneficial in various neurodegenerative diseases. These stem cells integrate and form connections with host cells. The problem with some stem cell treatments is the capability of these cells to form long axons from the spinal cord to the muscle cell and forming a junction with the muscle. Further research into the signaling mechanisms of the NMJ may find additional mechanisms by which transplanted cells may be of therapeutic benefit. 
- Ionotrophic receptors in the NMJ are receptors that allow ions to pass through them when they bind to acetylcholine
- Signal Transduction is the process by which an extracellular signaling molecule activates a membrane receptor that in turn alters intracellular molecules creating a response
- Farrugia M.E. 2002, "Myasthenia Gravis", JR Coll Physicians Edinb, vol 34, pp. 14-18.
- Leake, C. D. An Historical Account of Pharmacology to the Twentieth Century; Charles C. Thomas: Springfield, IL, 1975.
- Sneader, W. Drug Discovery: The Evolution of Modern Medicines; Wiley: New York, 1985
- Feldberg WS. Henry Hallett Dale, 1875-1968. Biogr Mem Fellows R Soc. 1970;16:77–174.
- Fatt P & Katz B (1951). An analysis of the end-plate potential recorded with an intra-cellular electrode. J Physiol 115, 320–370
- del Castillo J & Katz B (1954). Quantal components of the end-plate potential. J Physiol 124, 560–573
- Guyton AC, Hall JE: Textbook of Medical Physiology (2006) Elsevier Saunders, Philadelphia. P.87
- Guyton AC, Hall JE: Textbook of Medical Physiology (2006) Elsevier Saunders, Philadelphia. P.87
- Junqueira C.L. & Caraneiro J., 2005. Basic Histology, text & atlas, 11th edition. McGraw-Hill Companies.
- Stem cell-derived neurotrophic support for the neuromuscular junction in spinal muscular atrophy PMID20955113
Coordinator Comment to all Groups
I will add a general comment that will be the same to all groups under this heading.
Referencing Extension Problem
--Mark Hill 13:16, 3 May 2011 (EST) As mentioned in the lecture, I am aware of the referencing extension problem on your project pages. I have the following temporary solution, of removing the extension, so that groups can continue to add content to their project pages. I am also giving everyone a 1 week extension before the peer assessment.
This should only be done if your project page is not allowing you to save changes!
A. The Easy Way....
The following 4 steps can be done on the webpage or select all content in edit mode, copy and paste into a text editor. All steps must be completed before you attempt to save.
- In page edit mode, find all <pubmed> reference tags.
- Replace this tag with [http://www.ncbi.nlm.nih.gov/pubmed/ Note, there should be no spaces between the internet address and the pmid number.
- Now find all </pubmed> reference tags.
- Replace this second tag with ]
This will generate a numbered reference list that we can later fix up.
B. The Better Looking Result....
Whatever is between the <ref> </ref></pubmed> tags is what will appear in your reference list, so you can format the reference and link to appear in your reference list.
|2011 Projects: Synaptic Junctions | Gap Junctions | Tight Junctions | Desmosomes | Adherens Junctions | Neuromuscular Junction|