The Nervous System & Synaptic Transmission

Enteric nervous system: a system of sensory, motor and interneurons that extends from the oesophagus to the rectum Subdivisions of the Nervous System Features of a typical nerve cell (neuron) The 'Dendritic Tree' receives different inputs, both excitatory and inhibitory from many different neurons. The result hyperpolarising and depolarising influences converge and then spread across the cell body Features of a neurone and involvement If this convergence leads to sufficient dein neurotransmission polarisation of the axon hillock, then an action potential is fired from the neuron, which propagates along the axon to the nerve terminal 1 / 15 Neurons communicate with other cells (including other nerve cells) at Synpases · Each neuron can form thousands of links with other neurons. · A typical human brain can have 100-1000 trillion synapses · Functionally related neurons connect together to form neuronal networks/neural nets Synapses This communication can either by chemical (the most common form) or electrical The most well understood and studies example of a chemical synapse is the Skeletal Neuromuscular Junction (NMJ) where motor nerves, with their cells bodies in the CNS, communicate with skeletal muscle (the muscles that move the skeleton) to control movement - Both are types of membrane-bound receptors that are activated by the binding of neurotransmitter - Ionotropic receptors forms a ion channel pore and directly open the ion channel when the neurotransmitter binds Ionotropic vs Metabotropic receptors • Therefore, ionotropic receptors are fast-acting and responsible for producing rapid responses in the brain - Metabotropic receptors are couples with G proteins and do not have channels. They activate a secondary messenger that in turn will activate something 2 / 15 else • Therefore, they are slower acting and are involved in more complex signalling Presynaptic element Synaptic cleft Receptor proteins Postsynaptic element Neurotransmitter elimination or re-uptake Characteristics of a chemical synapse 1) A chemical that can act as a Neurotransmitter - The Neurotransmitter defines the nature of the signal - is it excitatory or inhibitory? - For neuronal-neuronal communication - Acetylcholine and Dopamine are both excitatory - mediated by cations ie Na+ Chemical Synaptic Transmission is a - GABA (Gamma aminobytyric acid) is multi-step process that requires chemiinhibitory - mediated by anions ie Clcal synapses to have -Acetylcholine 2) This must be stored in the presynaptic Dopamine cell GABA 3) A mechanism to trigger the release of the neurotransmitter into the synaptic cleft at the appropriate time 4) It must be capable of activating receptors found on the postsynaptic cell 5) A mechanism for removing the neurotransmitter so that the synaptic signal can be turned off There are many other neurotransmitters with some likely to yet be discovered. Normally, a given neuron will only release one neurotransmitter. But there ae 3 / 15 some examples of neutrons that release 2 simultaneously, eg ATP and NA in Chemical Neurotransmitters of the Ner- some nerves of the PNS. This is known as cotransmission vous System Neurotransmitters are produced in pre-synaptic nerve terminals by defined synthetic pathways. Different elements of these pathways eg, the synthetic enzymes, can be targeted by drugs to alter neurotransmission Chemical Neurotransmitters of the NerE.g. Inhibitors of tyrosine hydroxylase vous System: Neurotransmitter Synthesuch as alpha-methyl-tyrosine are used sis to inhibit noradrenaline synthesis in some forms of cancer (tumours of the adrenal gland But problems of widespread effects are observed as it will inhibit Noradrenaline synthesis throughout the nervous system ±methyl-tyrosine All Neurotransmitters once synthesised are stored in synaptic vesicles - these are small 'packets' of neurotransmitter surround by a phospholipid bilayer memChemical Neurotransmitters of the Ner- brane vous System: Neurotransmitter Storage Different neurotransmitters are stored in different types of vesicles. ACh - "Small, round, clear" vesicles 4 / 15 Noradrenaline - "Small, dense core" vesicles 1) The Vesicles protect the neurotransmitter from enzymes present in the cell cytoplasm that would destroy it. Eg: Monoamine oxidase which hydrolyses Monoamines such as Noradrenaline and Dopamine function of synaptic vesicle 2) It is a releasable form of neurotransmitter that can be released from the presynaptic terminal in a controlled manner by a process called exocytosis Drugs can also interfere with the storage of neurotransmitters Drugs such as Amphetamine, Tyramine, ephedrine enter via the 'uptake 1' channel and compete with NA to enter the vesicles via VMAT displacing NA from storage causing leakage into the synaptic gap Drugs can also interfere with the storage Amphetamine also has secondary efof neurotransmitters fects inhibiting MAO, increasing the concentration of free NA for release into the synaptic gap Reserpine also blocks the VMAT channel preventing NA uptake into vesicles. This leads to the unprotected NA being 5 / 15 broken down by MAO thus depleting the terminal of NA 1) Nerve impulse (the action potential) arrives at the presynaptic terminal causing depolarisation 2) This depolarisation causes voltage-gated Ca2+ channels to open causing an increase in the concentration of Ca2+ ions in the presynaptic terminal 3) The neurotransmitter is released into Chemical Neurotransmitters of the Ner- the synaptic cleft by exocytosis, where vous System: Neurotransmitter Release the membrane of the vesicle fuses with the membrane of the nerve terminal Ca2+ ions facilitate trafficking of vesicles to the cell membrane along microtubules of the cytoskeleton. This brings the vesicles into contact with tethering factors allowing for 'docking and priming' of vesicles. This is facilitated by Synaptobrevin interacting with Syntaxin and SNAP-25 Full membrane fusion and neurotrans6 / 15 mitter release is triggered by the binding of Ca2+ to synaptotagmin Drugs can again interfere with this process. In the case of ACh terminals Botulinum toxin destroys SNAP-25 Exocytosis - A complex process Inhibits Exocytosis and therefore ACh release v-SNARES: Synaptobrevin, Synaptotagmin t-SNARES: Syntaxin, SNAP-25 • Neurotransmitter release is regulated by negative feedback mechanisms facilitated by autoreceptors • Presynaptic expressed ±2receptors • Activation of autoreceptors (typically Chemical Neurotransmitters of the NerGi/o) coupled inhibit exocytosis vous System: Neurotransmitter Release• Stimulation of these receptors (eg negative feedback Clonidine) can be used to inhibit neurotransmitter release • Autoreceptors can be found on neurones mediated by other neurotransmitters to inhibit exocytosis All neurotransmitters are agonists at their respective receptors - Receptor Activation is critical for signal transduction 7 / 15 Ionotropic • Receptor-operated (ligand-gated) ion channels made up of several subunits • Agonist activation induces a conformational change opening the ion pore • Mediate fast synaptic channels • Examples include • Nicotinic AChR - non-selective cation channel • NMDA and AMPA Glutamate receptors - non-selective cation channel • 5HT3 Receptor - non-selective cation channel • GABAA Receptor - selective chloride channel Metabotropic receptor There are 2 main classes of receptors in • G Protein Coupled receptor - 7 Transthe nervous system membrane spanning alpha-helical domains • Agonist activation induces a conformational change causing GTP/GDP exchange and dissociation of the alpha subunits from the beta/gamma subunits • Mediate slower synaptic transmission coupled to 2nd messenger cascades • Examples include • Muscarinic ACh Receptors • Metabotropic glutamate receptors (mGlu1-mGlu8) • All 5-HT receptors except for 5-HT3 • GABAB Receptor • Dopamine Receptors (D1-D5) 8 / 15 The Ion channel is contained within a multiprotein complex. The nicotinic ACh is a pentameric (5 subunits) - Nicotinic Ach is a receptor which responds to the neurotransmitter acetylcholine The channel is normally closed, but opens when the neurotransmitter binds to the receptor Ionotropic Receptors Depending on which ions flow through the channel (selective permeability) the effect of the neurotransmitter will be to either depolarise or hyperpolarise the post synaptic membrane nAChR - non selective cation channel GABAA Receptor - Selective Chloride Channel Depolarisation will excite the post synaptic cell (increasing the likelihood of and action potential being fired), this is called an excitatory post synaptic potential (EPSP) Hyperpolarisation will inhibit inhibitory post synaptic potential (IPSP) 9 / 15 All Metabotropic receptors are G Protein coupled receptors and are made up of - 7 Transmembrane spanning alpha helical domains - 1 Heterotrimeric GTP binding G Protein All GPCRS have the same overall structure, with a extracellular (outside the cell) N-terminus, and an intracellular (inside the cell) C-terminus Metabotropic Receptors Activation of the receptor by its endogenous ligand (agonist) triggers a cascade of biochemical (metabolic) reactions within the post synaptic cell E.g. Inhibition/Activation of enzymes such as Adenylyl Cyclase, modulation of ion channel activity, or gene transcription Different Metabotropic receptors can couple to different G Proteins (Gi (inhibitory), Gs (stimulatory), Gq (stimulatory). This means different receptors can stimulate different signalling cascades therefore different functional outcomes This gives more selectivity of function over Ionotropic receptors - which are selective only to their ion Remember from earlier.... • Nerve cells have a resting membrane potential ~-70mV • This membrane potential can be changed by increasing/decreasing the permeability of the membrane to different ions • The permeability of the membrane to different ions is regulated by the opening and closing of specific ion channels ie 10 / 15 Na+, K+, Ca2+ and Cl• Therefore the membrane potential is regulated by the opening/closing of these ion channels • The understanding of ion channels is key to understanding the operation of nerve cells The Resting Potential of a cell is approximately -55 to -70mV and is maintained principally by Na+ and K+ ions The Action Potential is triggered by the influx of Na+ and K+ ions - this is caused a depolarisation This is mediated by Sodium and Potassium Voltage-gated channels The Action Potential The Action Potential is driven first by opening of Na+ channels leading to Na+ influx to reach ENa (depolarisation), The Na+ channels then inactivate and close K+ channels then open leading to K+ efflux which drives the membrane potential back down towards EK (repolarisation) 11 / 15 Following the depolarisation of the presynaptic terminal ACh is released from vesicles by exocystosis ACh stimulates the nictonic ACh receptor (an Ionotropic receptor), opening the non-selective cation channel --- Na+ influx Na+ influx induces a depolarisation moving the membrane potential towards the threshold for firing an action potential (-55mV) Post Synaptic Potentials -Using a ACh regulated synapse as an This is called the Excitatory Post Synapexample tic Potential (EPSP) This depolarises the axon hillock region of the cell, which if large enough (possibly through the summation of many EPSPs) causes the generation of an action potential In the case of a inhibitory neurotransmitter for example GABA, the influx of Chloride ions moves the membrane potential In the case of a inhibitory neurotransmitaway from the threshold for an action ter potential Inhibitory Post Synaptic Potential (IPSP) 12 / 15 Action potential • Propagated along the axon • All or nothing • Transient (approx. 2 - 5 msec) • Coordinated opening and closing of voltage-gated sodium and potassium Action Potentials vs Synaptic Potentials channels • Followed by a distinct refractory period Synaptic potential - Regulate the firing of the action potential - Graded; more receptors activated bigger the synaptic potential - Peak within 10 - 100 msec depending on type of receptor involved Action Potentials vs Synaptic Potentials - Cause by opening of channels controlled by neurotransmitter receptors - End when neurotransmitter diffuses from the receptor and is removed from the synapse 13 / 15 Chemical Synaptic Transmission is terminated when the neurotransmitter is removed from the synapse. This can be done by 3 main mechanisms 1) Simple Diffusion away from the synapse 2) Uptake of neurotransmitter into the presynaptic terminal or by other cells e.g. Uptake of NA through the noradrenaline transporter (NET) 3) Enzymatic degradation e.g. Breakdown of ACh to Acetyl Coenzyme A and Chemical Neurotransmitters of the Ner- Choline by Acetylcholinesterase (AChE) vous System: Neurotransmitter Removal or Monoamine Oxidase breakdown of NA/DA or 5-HT We can interfere with this process using drugs as well AChE inhibitors are used to treat Alzheimer's Disease whilst Selective Serotonin Reuptake Inhibitors (SSRIs) are used to treat......... areas for drug targeting 14 / 15 • Common for glial to glial cell communication, but rare in neuronal signalling in mature mammals • No signalling specificity • Narrow synaptic "cleft" (~2 nm) • Mediated by direct interactions between gap junction proteins e.g. connexins Electrical Synaptic Transmission: A Brief • 'bidirectional' communication • Fast transmission (<1 msec synaptic Outline delay)• summary 15 / 15