Pharmacology- neuromuscular blocking agents Flashcards
describe the function of the pre synaptic portion of the neuromuscular junction
The presynaptic portion of the NMJ is responsible for neurotransmitter (ACh) synthesis, uptake and storage of neurotransmitter into synaptic vesicles, ACh release and reuptake of choline after its hydrolysis, and control of ion flow across the nerve terminal cell membrane.
describe neuromuscular transmission.
The classic model of neuromuscular transmission is straightforward. The nerve synthesizes acetylcholine (ACh), which is stored in small uniformly sized membrane vesicles called synaptic vesicles. When the distal motor nerve is stimulated by an action potential, it causes voltage-gated calcium ion (Ca 2+ ) channels to open, giving rise to an abrupt, rapid, transient increase in nerve terminal Ca 2+ concentration. The elevated Ca 2+ concentration triggers fusion of ACh-containing synaptic vesicles to the presynaptic membrane, where they release ACh into the synaptic cleft that separates the nerve from the muscle. ACh released into the cleft binds to nicotinic acetylcholine receptors (AChRs) on the surface of the postjunctional muscle membrane. These heteropentameric ligand-gated ion channels are nonselective caption channels in the postjunctional membrane that allow influx of Na + , resulting in endplate depolarization and muscle contraction. Much of the released ACh is instantaneously hydrolyzed by synaptic acetylcholinesterase present in the cleft and never reaches its target. The excess release of ACh contributes to a margin of safety that ensures successful neurotransmission
Describe the course and divisions of a typical motor axon
Each motor neuron represents a large myelinated axon that extends from the ventral horn of the spinal cord or medulla to the NMJ. As it approaches the target muscle, the myelinated motor axon divides into 20 to 100 unmyelinated fibers, each of which innervates a single muscle fiber. The functional group of terminal nerve fibers and the muscle fibers they serve is called a motor unit . The terminal myelin-free portion of the nerve axon is encapsulated by a Schwann cell.
Schwann cells importantly contribute to presynaptic and postsynaptic maturation and is integral to the efficient communication between the highly concentrated postsynaptic AChRs and perfectly aligned presynaptic ACh release sites
describe the synaptic cleft of the neuro muscular junction
The junctional or synaptic cleft is the gap (~50 nm) between the nerve terminal ending and the muscle membrane.
The cleft contains a basal lamina composed of a variety of cell and other adhesion macromolecules that modulate neuromuscular signaling processes. These molecules include acetylcholinesterase, α- and β-laminin, and collagen.
After release from the nerve terminal, ACh diffuses the short distance across the synaptic cleft to the postsynaptic membrane. The high concentration of ACh in combination with the short distance between the site of release and the postsynaptic membrane ensures rapid transmission. Approximately 50% of the released ACh is either degraded by acetylcholinesterase or diffuses out of the cleft before it reaches its target.
Acetylcholinesterase is anchored to the basal lamina, where it degrades ACh into acetate and choline, thereby terminating the activity of the transmitter. Choline is then taken up into the presynaptic terminal by a choline transporter proteins for resynthesis of ACh within the nerve terminal.
describe the post synaptic membrane of the neuomuscular junction
The muscle membrane is highly corrugated with deep invaginations representing primary (shallower) and secondary (deeper) clefts such that the total surface area of each endplate is very large. The depths of these folds vary between muscle types and species. The shoulders of the folds contain high densities of AChRs (~ 5 million in each junction) anchored into the muscle cell membrane by a complex system of cytoskeletal proteins. AChRs are sparse in the depths between the folds, which contain a high density of voltage-gated Na + channels for amplification of AChR-induced depolarization.
The perijunctional zone is the area of muscle that lies immediately beyond the junctional area. It serves the critical function of transducing the signal from the junction into deeper regions of the muscle cell. The perijunctional zone contains a high density of Na + channels that promote amplification of the transduced signal, culminating in muscle contraction.
Describe the synaptic vessicles and the effect of Ca on their release
Synaptic vesicles containing neurotransmitter are clustered along thickened, electron-dense patches of membrane in the terminal portion of the nerve referred to as active zones.
Voltage-gated Ca 2+ channels permit Ca 2+ to enter the nerve and initiate the process that ultimately triggers vesicle release. The close proximity of voltage-gated Ca 2+ channels to the vesicle fusion apparatus is believed to contribute to the rapidity with which ACh is released (~200 ns).
The number of quanta of ACh released by a stimulated nerve is strongly influenced by the concentration of extracellular ionized Ca 2+ and its influx into the nerve. Doubling extracellular Ca 2+ concentration results in a 16-fold increase in quantal release.
The amount of ACh released by each nerve impulse is large, at least 200 quanta, consisting of about 5000 ACh molecules each, and about 500,000 AChRs are activated.
describe the process of exocytosis of the synaptic vesicles at the neuromuscular junction
The complex process of docking, fusion, and release of neurotransmitter from synaptic vesicles is called exocytosis . Three proteins, synaptobrevin, syntaxin, and synaptosomal-associated protein 25 (SNAP-25), within the group of soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins have key roles in the process of exocytosis. A complex of syntaxin and SNAP-25 is attached to the plasma membrane. After initial contact, synaptobrevin on the vesicle forms a ternary complex with syntaxin and SNAP-25 that consists of a zippered helical bundle. This complex forces the vesicle close to the nerve terminal membrane at the active zone (release site).
Synaptotagmin, a protein on the vesicular membrane that acts as the Ca 2+ sensor, localizes the vesicles to synaptic zones rich in Ca 2+ channels and stabilizes the vesicles in the docked state. After fusion and exocytosis, the used vesicle and membrane parts are recycled through an active process into the nerve terminal; there they are reused to form new vesicles (endocytosis), filled with ACh, and then transported to the active sites for release.
what subtypes of calcium channels are associated with the release of Acetylecholine?
Of the several subtypes of Ca 2+ channels, four voltage-gated Ca 2+ channels are important for spontaneous and evoked release of ACh: P/Q-, N-, L-, and R-type channels. P/Q type channels are found only in nerve terminals immediately adjacent to the active zones and are probably the major type responsible for the normal release of neurotransmitter.
describe the structure of acetylcholine receptors
Nicotinic AChRs belong to the cys-loop superfamily of pentameric ligand-gated ion channels that share a common architecture, with five subunits surrounding a central ion-conducting pore. Each subunit is built on four transmembrane segments with the second transmembrane segment lining the pore. Each subunit is composed of approximately 400 to 500 amino acids. The AChRs are synthesized in muscle cells and anchored to the endplate membrane by the 43-kDa protein rapsyn. Four subtypes of perijunctional AChRs are of clinical importance: the presynaptic α 3 β 2 , the postsynaptic 2α 1 β 1 δε or 2α 1 β 1 δγ and the α 7 AChRs located both in terminal Schwann cell and postsynaptically on the muscle. The α subunits contain two adjacent cysteines essential for ACh binding and the non-α subunits contribute to the specificity and stability of each receptor isoform.
Although many potential receptors are possible by combining different subunits, only a few have been found to be of biologic importance. In the NMJ, the α 3 β2 (neuronal) subtype is found in the presynaptic nerve ending. The 2α 1 β 1 δγ and α 7 AChRs are found postsynaptically during development and denervation and in other acquired pathologic states (e.g., immobilization and burns).
