MD224 Lect 1 Principles of neurotransmission.pdf

Principles of CNS neurotransmission Prof. Adrienne Gorman School of Biological and Chemical Sciences [email protected] 1 Topic 1 Principles of CNS neurotransmission 2 Nervous system • Neurons: • 1011 ie, 100,000,000,000 • Each with 1,000-10,000 connections, ie, 1014 -1015 co...

Principles of CNS neurotransmission Prof. Adrienne Gorman School of Biological and Chemical Sciences [email protected] 1 Topic 1 Principles of CNS neurotransmission 2 Nervous system • Neurons: • 1011 ie, 100,000,000,000 • Each with 1,000-10,000 connections, ie, 1014 -1015 connections Communicate information • Glia (or neuroglia): from ‘glue’ • • • • Astrocytes Oligodendrocytes Schwann cells Microglia Supporting function 3 Input Integration of signal Output 4 Synapse Specialized sites where neurons communicate with other cells via neurotransmitters 5 Principles of neurotransmission, 4 steps 1. Neurotransmitter synthesised and stored in high concentration in nerve terminals 2. Released upon stimulation of nerves 3. Stimulates target organs/cells 4. Active mechanisms to terminate its effect 6 Step 1 in neurotransmission Synthesis and storage of neurotransmitter in high concentration in nerve terminals Synthesis is usually in the cytosol Dendrite 7 Neurotransmitter classification • Classical (small molecule) NTs • Neuropeptides (non-classical NTs) • Short peptides (3-36 amino acids long) that are neuroactive, e.g., Substance P • Unconventional • Nitric oxide, NO • Carbon monoxide, CO • Arachidonic acid 8 Classical (small molecule) neurotransmitters 9 Transport of classical NT into synaptic vesicles H+-ATPase Vesicular neurotransmitter transporter Dependent on two proteins: • H+-ATPase (proton pump) – creates H+ (proton) gradient across vesicle membrane • H+ /neurotransmitter antiporter 10 Step 2 in neurotransmission Release of the neurotransmitter upon stimulation of the neuron 11 Neurotransmitter release • Exocytosis of synaptic vesicles is tightly coupled to arrival of an action potential at the axon terminus • NT release is also dependent upon Ca2+ influx into the presynaptic nerve terminal 12 Action potential Electrical signal that travels from neuronal cell body down the axon to the axon terminus Characterised by high speed (up to 120 m/sec) with no loss of signal over long distances 13 No diminution of signal: Myelin sheath provides insulation Oligodendrocytes in CNS and Schwann cells in PNS wrap themselves around axons to provide insulation along the axon Composition of myelin = 70-80% lipid; 20-30% protein 14 Role of Ca2+ in NT release • This electrical signal must be converted into a chemical signal: Ca2+ • Voltage-gated Ca2+ channels located in the nerve terminal adjacent to synaptic vesicles [Ca2+]: 80-100 nM  1-100 M • Increase in Ca2+ is highly localized 15 Increase in intracellular Ca2+ is highly localized Urbano F J et al. PNAS 2003;100:3491-3496 ©2003 by The National Academy of Sciences 16 What are the molecular mechanisms of exocytosis during neurotransmitter release? 17 Synaptic vesicle proteins Takamori et al, (2006) Cell 127, 831–846 18 SNARE proteins Control fusion of the two membranes V-SNARES and T-SNARES 19 SNARE complex 20 Synaptotagmin Ca2+-sensing protein 21 Diseases that affect the presynaptic terminal • Some myasthenic syndromes • Present as muscle weakness that worsens with exertion • Caused by abnormal transmission at neuromuscular synapses • Lambert-Eaton myasthenic syndrome (LEMS) – an autoimmune disease • Clostridium infection (toxins) 22 Botulinum toxin • From clostridium botulinum which causes food poisoning and paralysis • Heavy chain involved in entry into neurons in the neuromuscular junction (NMJ) Catalytic domain Translocation domain Receptor binding domain • Light chain has protease activity 23 Toxins That Affect Transmitter Release 24 Uses of botulinum toxin 25 Medical uses of Botox: several FDA approvals and many patents pending • 1980 – crossed eyes (Strabismus) • 1985 – uncontrolled blinking (Blepharospasm) • 1993 - excessive sweating (Hyperhidrosis) • 2002 - Glabellar frown lines • 2010 - Chronic migraines Made by Allergan (Abbvie), in Dublin and Westport 26 Step 3 in neurotransmission When it is released into the synaptic cleft, the neurotransmitter binds and activates receptors on the post-synaptic cell membrane 27 Neurotransmitter receptors Two main kinds of NT receptor 1. Ionotropic • Ligand-gated ion channels 2. Metabotropic • G protein coupled receptors (GPCR) Many classical NTs can bind both to specific ionotropic and metabotropic receptors 28 Ionotropic receptors are generally heteromeric Individual receptors are made of multiple subunits Glutamate receptors 29 Ionotropic receptors: heteromeric ion channels NT binding stimulates rapid opening of ion channel Mediate fast responses Monomer Heteromeric multisubunit complexes 30 Metabotropic receptors • Single polypeptide that spans membrane 7 times • G protein coupled receptors (GPCR) • Adenylate cyclase • Phospholipase C or A • Ion channels • Reponses tend to be slower than for ionotropic receptors and of longer duration (seconds – hours) 31 Metabotropic receptors Several subtypes that bind to each neurotransmitter Ligand Glutamate Acetylcholine 32 Step 4 in neurotransmission Termination of the effect of the neurotransmitter 33 Main mechanisms for termination of response 1. Enzymatic degradation 2. Uptake into: a) Neuron via specific membrane transport protein, then uptake into synaptic vesicles b) Surrounding astrocytes 3. Diffusion away from synaptic cleft 34