The Synaptic transmission M.Bayat PhD Session 4 The Synaptic transmission M.Bayat PhD The Sanger Institute

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Two principal kinds of synapses: electrical and chemical Where nerve impulses convert to neurotransmitters

Gap junctions are formed where hexameric pores called connexons connect with one between cells

Electrical Synapses Allows the direct transfer of ionic current from one cell to the next. Gap Junction is composed of 6 connexins that make up a connexon. (Pore size = 2nm) Ions can flow bidirectionally. Cells are electronically coupled. Conduction speed is very fast. Found in neuronal pathways associated with escape reflexes or in neurons that need to be synchronized. Common in non neuronal cells. Important in development

Electrical synapses are built for speed

Chemical synapse in neuromuscular junction

Synaptic cleft

Synaptic cleft

Delay in chemical synapse Delay of about 1 ms

Requirements of Chemical Synaptic Transmission. Mechanism for synthesizing and packing neurotransmitter into vesicles. Mechanism for neurotransmitter release Mechanism for producing an electrical or biochemical response to neurotransmitter in postsynaptic neuron. Mechanism for removing transmitter from synaptic cleft. must be carried out very rapidly.

Mechanism for synthesizing and packing neurotransmitter into vesicles.

Criteria that define a neurotransmitter: Must be present at presynaptic terminal Must be released by depolarization, Ca++-dependent Specific receptors must be present

Neurotransmitters may be either small molecules or peptides Mechanisms and sites of synthesis are different Small molecule transmitters are synthesized at terminals, packaged into small clear-core vesicles (often referred to as ‘synaptic vesicles’ Peptides, or neuropeptides are synthesized in the endoplasmic reticulum and transported to the synapse, sometimes they are processed along the way. Neuropeptides are packaged in large dense-core vesicles eptide

peptide

Neurotransmitter Synthesis and Storage Synthesis of peptide neurotransmitters Synthesis of amine and amino acids

Mechanism for neurotransmitter release

Neurotransmitter Release Action potential enters the axon terminal. Voltage gated Ca++ channels open. Ca++ activates proteins in the vesicle and active zone. Activated proteins causes synaptic vesicles to fuse with membrane. Neurotransmitter is released via exocytosis. Note: Peptide release requires high frequency action potentials and is slower (50 msec vs. 0.2 msec).

Active zone

With action potential Without action potential 1 vesicle in sec = quantal release May produce unit potential in post synaptic 150 vesicle in 1 msec= 100000/sec at the nerve-muscle synapse

Synapsin Rab SNARE PROTEINS V-SNARE VAMP (synaptobervin)- synaptotagmin T-SNARE SNAP 25 -syntaxin

Proteins have been identified that are thought to (1) restrain the membrane in response to Ca vesicles so as to prevent their accidental mobilization (2) target the freed vesicles to the active zone, (3) dock the targeted vesicles at the active zone and prime them for fusion, (4) allow fusion and exocytosis (5) retrieve the fused membrane by endocytosis

The importance of the SNARE proteins in synaptic transmission is emphasized by the finding that all three proteins are targets of various clostridial neurotoxins. All of these toxins act by inhibiting synaptic transmission.

Mobilization The vesicles outside the active zone represent a reserve pool of transmitter. They do not move about freely in the terminal but rather are restrained or anchored to a network of cytoskeletal filaments by the synapsins, a family of four proteins (Ia, Ib, IIa, and IIb) When the nerve terminal is depolarized and Ca2+phosphorylated by the Ca/calmodulin-dependent protein kinase. Phosphorylation frees the vesicles from the cytoskeletal constraint, allowing them to move into the active zone targeting or trafficking The targeting of synaptic vesicles to docking sites for release may be carried out by Rab3A and Rab3C, These Rab proteins bind to synaptic vesicles Hydrolysis of the GTP bound to Rab, converting it to GDP, may be important for the efficient targeting of synaptic vesicles to their appropriate sites of docking.

Docking Docked vesicles lie close to plasma membrane (within 30 nm) According to this theory, specific integral proteins in the vesicle membrane (vesicle-SNARES, or v-SNARES) bind to specific receptor proteins in the target membrane (target membrane or t-SNARE) In the brain two t-SNARES have been identified: syntaxin, a nerve terminal integral membrane protein, and SNAP-25, a peripheral membrane protein of 25 kDa mass. In the synaptic vesicle the integral membrane protein VAMP (or synaptobrevin) has been identified as the v-SNARE. Priming Primed vesicles can be induced to fuse with the plasma membrane by sustained depolarization, high K+, elevated Ca++, hypertonic sucrose treatment Fusion Vesicles fuse with the plasma membrane to release transmitter. Physiologically this occurs near calcium channels, but can be induced experimentally over larger area (see ‘priming’). The ‘active zone’ is the site of physiological release, and can sometimes be recognized as an electron-dense structure. .

Neurotransmitter Recovery and Degradation Neurotransmitters must be cleared from the synapse to permit another round of synaptic transmission. Methods: Diffusion Enzymatic degradation in the synapse. Presynaptic reuptake followed by degradation or recycling. Uptake by glia Uptake by the postsynaptic neuron and desensitization.

Anticholinesterases drugs as: myasthenia gravis, a disorder of function at the synapse between cholinergic motor neurons and skeletal muscle.

Dopamine release and reuptake

Cocaine inhibits dopamine reuptake