pulse to postsynaptic fiber pulse to presynaptic fiber pulse to postsynaptic fiber
The Electrical Gap Junction
The electrical gap junction has been isolated from nervous tissue and characterized. All gap junctions studied consist of pairs of protein cylinders called connex-ons. One connexon is presynaptic, and the other is postsynaptic. The two connexons meet in the extracellular gap between the two cells, through homophilic interactions, and the two hemichannel cylinders align end-to-end to form a hollow tube, with a central channel, about 1.5-2.0 nm in diameter, which connects the cytoplasm of the two cells.
The connexon itself consists of six identical subunits, called connexins, each about 7.5 nm long, which are hexagonally arranged in the cell membrane. The gap junction brings cells relatively close to each other; at the gap junction the pre-and postsynaptic cells are about 3.5 nm apart, whereas usually and at chemical synapses the neurons are about 20 nm apart.
The channels may open through the rotation of the connexins, which creates an open pore through the connexon. The channel may close through the tilting of the connexins at the cytoplasmic end as they slide against each other, which causes a clockwise rotation of the base of the con-nexon. This form of conformational change may be a common feature of ion channel opening generally.
From gene cloning experiments with samples from heart, liver and the lens, it appears that the connexons may be members of a larger gene family. There are regions of close homology, particularly within the hydrophobic domains of the connexons that span the cell membrane, as well as within sequences corresponding to extracellular domains of the connexon, which are involved in the homophilic reactions between the hemichannels. There is less homology within sequences within regions corresponding to the cytoplasmic domain of the connexon, and this may explain partly why gap junctions vary between tissues with respect to their sensitivity to chemical mediators.
dosed channel open channel dosed channel open channel model of a single connexin- a subunit of the connexon presynaptic »11
20nm channel connects cytoplasm of both cells extracellular.
20nm electrical gap junction channel connects cytoplasm of both cells
Chemical synapses are specialized structures that enable the chemical transfer of information from one cell to another. They may occur between nerves, as happens most frequently in the central nervous system, or between nerves and effector tissues, such as muscle, glands, and sensory organs. At a typical chemical synapse, a branch of the afferent or presynaptic axon swells at its terminus to form a so-called bouton, which is very close to, but does not physically touch, the specialized post-synaptic side of the synapse. Thus, a synaptic cleft, typically 20 nm wide, is formed between the two communicating cells. The fluid-filled gap between the two cells prohibits the direct transfer of electrical current from one cell to the next. Transfer is effected instead through the rapid diffusion of a chemical substance called a neurotransmitter across the gap to the postsynaptic cell, where it may produce either an excitatory or inhibitory postsynaptic potential.
A synapse between presynaptic axon and postsynaptic soma (cell body) is called axosomatic; most neurons have fine cyto-plasmic processes called dendrites, which may synapse with an incoming axon, to form axodendritic synapses. Dendrites from different neurons may synapse to form dendrodendritic synapses. Axons may synapse with axons from other neurons; these are called axoaxonic synapses (see also p. 73).
There are very pronounced thickenings or increased densities of the membrane on both sides of the synapse; the presynaptic thickening may be due to the clustering of synaptic vesicles filled with neurotrans-mitter molecules. The neurotransmitter molecules are packaged into vesicles, which fuse with the membrane, and their contents are extruded from the presynaptic cell into the synaptic cleft.
Small processes, or spines, are formed on dendrites, and these dendritic spines form synapses with other dendrites. From electron microscope studies of synapses on spines, synapses have been classified by the width of the synaptic cleft and the distribution of synaptic density. Type 1 synapses, for example, are characterised by a wider synaptic cleft and a denser region of synaptic thickening than occurs at Type 2 synapses. The classification may have functional significance, since in the pyramidal cells of the cerebral cortex, Type 1 synapses occur on spines projecting from apical or basal dendrites, whereas Type 2 synapses occur on the soma of the pyramidal cells of the cerebral cortex.
Synapses may also be complex, where a single spine may form several synapses with an incoming axon, as occurs most commonly in certain cell types in the central nervous system; complex synapses of this type have been described in, for example, pyramidal cells of the hippocampus.
synaptic knob presynaptl axoi synaptic knob presynaptl axoi
nucleus with nucleolus postsynaptic axon myelin sheath postsynaptic thickening postsynaptic thickening
presynaptic bouton vesicles dendritii synaptic sPine cleft mitochondrion dendriti of hippocampal cell vesicle cluster vesicle cluster dendriti of hippocampal cell
tubule complex synapse on hippocampal cell dendrite tubule complex synapse on hippocampal cell dendrite
(after Whittaker and Cray, 1962)
The neuromuscular junction (NMJ) is the synapse where electrical information is chemically transmitted from nerve to skeletal muscle. The nerve is the motoneuron, which has its cell body in the spinal cord, and whose axon terminates at the motor end plate of the muscle. The NMJ has been extensively studied. It was one of the first synapses to be characterized anatomically, physiologically, and biochemically, because the muscle cell is large enough to take several electrodes, and because the NMJ can be seen under the light microscope.
The electrical information (action potential) is transduced to a chemical signal in the form of a neurotransmitter, acetylcholine (ACh; see also p. 101), which is transduced back to an action potential in the muscle. The action potential is then transduced to mechanical work as a muscle twitch. Usually, one axon innervates one fiber.
Shortly before the axon arrives at the end plate, it loses the myelin sheath and forms several thin branches. At the end plate, the axon terminal swells into the bouton, which is covered by a layer of Schwann cells. The presynaptic bouton contains synaptic vesicles, filled with ACh. The bouton occupies a depression in the muscle fiber surface. The postsynaptic membrane lies approximately 50 nm opposite, and is extensively folded opposite the bouton, with a high density of acetyl-choline receptors. ACh receptors have been visualized at the NMJ using auto-radiography. ACh receptors were labeled with radioactive antibodies to the receptors, or with a snake venom, a-bun-garotoxin, which binds ACh receptors irreversibly. (ACh receptors at the NMJ and at autonomic ganglia are termed 'nicotinic', because they were originally studied using the partial agonist, nicotine.)
At the crest of the junctional fold, the density of ACh receptors is about 104 receptors per pm2. There is a connective tissue layer over the muscle, the basement membrane, or basal lamina, consisting of glycoproteins and collagen. The basement membrane contains a high density of the enzyme acetylcholinesterase, one of the fastest-acting enzymes secreted from the postsynaptic cell, mainly in the synaptic folds. Acetylcholinesterase breaks down ACh and is the mechanism whereby the action of ACh is rapidly terminated. Acetyl-cholinesterase can be inhibited by a clinically important group of enzyme inhibitors called anticholinesterases. Short-acting anticholinesterases, such as edro-phonium can be used to diagnose the muscle-weakening disease myasthenia gravis, while longer-acting anticho-linesterases, such as neostigmine, are used in treatment.
myelin cell nucleus myelin cell nucleus
receptor-rich region motor nerve endings on smooth muscle receptor-rich region motor nerve endings on smooth muscle motonei motonei
mitochondrion vesicle presynaptic_
membrane postsynaptii membrane acetylcholine receptors acetylcholinesterase (AChE)
membrane postsynaptii membrane
motoneuron mitochondrion motoneuron junctional fold
Acetylcholine (ACh) is the neurotransmitter at the neuromuscular junction. Chemically, it is a choline ester. ACh is synthesized at the cholinergic nerve terminal from cholineand acetyl coenzyme A (ace-tyl CoA). The reaction is catalyzed by the enzyme choline acetyltransferase (also referred to sometimes as choline acety-lase). Newly synthesized ACh is packaged into vesicles, which fuse with the cell membrane and release their contents into the synaptic cleft.
ACh release from the nerve terminal at the NMJ is effected by several mechanisms. These are: (i) the formation of the vesicles; (ii) the presence of the active zone, which is the region of nerve membrane proteins specialized for neu-rotransmitter release, and (iii) the voltage-gated Ca2+ channels. Release occurs in quanta, or packages, each of which involves several thousand molecules of ACh. Release occurs spontaneously at a relatively low rate. A much larger quantal release of ACh occurs in response to the arrival at the nerve terminal of the impulse, or action potential (AP). The AP causes the influx of Ca2+ ions through voltage-gated channels into the nerve terminal, and in-tracellular Ca2+ triggers the fusion of vesicles with the nerve terminal membrane. The released ACh diffuses across the syn-aptic cleft to nicotinic ACh receptors in crests of the folds of the postsynaptic muscle membrane. Two ACh molecules bind to one receptor, and this results in the opening of the receptor channel to Na+. The resultant stimulation of the muscle end plate is called an end plate potential (EPP; see also p. 105). One vesicle delivers one quantum of ACh to the receptors, and one quantum generates a miniature end plate potential (MEPP; see also p. 105). The release of ACh from the nerve terminal may be blocked by pharmacological intervention. Ions such as Co2+ and Mg2+, and neurotoxins such as botulinum toxin will prevent fusion of the vesicles with the membrane.
Important pharmacological and therapeutic agents, such as tubocurarine and suxamethonium reduce the effects of ACh on the receptors by blocking the binding and effects of the neurotransmitter on the receptor.
Inactivation of ACh as a neurotransmit-ter is rapidly accomplished through the action of the enzyme acetylcho-linesterase. This enzyme inactivates ACh by hydrolyzing it to choline and acetate. Choline is taken up by the nerve terminal for recycling in the ACh synthetic pathway, and the uptake process can be blocked by the compound hemicholinium. Although interesting as an experimental tool, hemi-cholinium has no use therapeutically. Acetylcholinesterase occurs mainly on the postsynaptic side in the muscle; it is known to be secreted into the cleft from the basement membrane of the end plate. The enzyme can be blocked by a series of important chemicals, the anticholinester-ases.
acetylcholine (ACh) • extracellular closed
acetylcholine - receptor interaction acetylcholim molecule
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