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NEUROTRANSMITTERS AND RECEPTORS The Structure of the Neuron • Playing the piano, driving a car, or hitting a tennis ball depends, at one level, on exact muscle coordination. • But if we consider how the muscles can be activated so precisely, we see that more fundamental processes are involved. • For the muscles to produce the complex movements that make up any meaningful physical activity, the brain has to provide the right messages to them and coordinate those messages. The Structure of the Neuron • Neurons , or nerve cells, are the basic elements of the nervous system. • Many of the body’s neurons receive signals from the environment or relay the nervous system’s messages to muscles and other target cells, but the vast majority of neurons communicate only with other neurons in the elaborate information system that regulates behavior. • The messages that travel through a neuron are electrical in nature. Although there are exceptions, those electrical messages, or impulses , generally move across neurons in one direction only, as if they were traveling on a one-way street. How Neurons Fire What is a synapse? • A junction where the axon or some other portion of one cell (= presynaptic cell) terminates on the dendrites, soma, or axon of another neuron (post synaptic cell). Types of synapses ( functional classification) Two types of communicating junctions or synapses: Electrical synapses via gap junctions, chemical synapses involving neurotransmitters •A.Electrical synapse •… •B.Chemical synapse •Almost all synapses used for signal transmission in the CNS of human being are chemical synapses. • i.e. first neuron secretes a chemical substance called neurotransmitter at the synapse to act on receptor on the next neuron to excite it, inhibit or modify its sensitivity. Structure of an electrical synapse Chemical synapse Figure 48.12 A chemical synapse CHEMICAL ACTIVITY AT SYNAPSE: Excitatoy Postsynaptic Potential (EPSP) Inhibitory post-synaptic potentials (IPSP) • The excitatory • Stim. of some inputs neurotransmitter opens [=pre-synaptic terminals] Na+ or Ca++ channels hyperpolarization of depolarization of the area the post-synaptic memb. under the pre-synaptic which is the IPSP. membrane. Classification of neurotransmission Fast neurotransmission Neurotransmitter directly activates ligand-gated ion channel receptor Neuromodulation Neurotransmitter binds to G-protein coupled receptor to activate a chemical signaling cascade Synaptic inhibition • Direct inhibition • Post-synaptic inhibition, e.g. some interneurones in sp. cord that inhibit antagonist muscles. Neurotransmitter secreted is Glycine. • Occurs when an inhibitory neuron (releasing inhibitory substance) act on a postsynaptic neuron leading to its hyperpolarization due to opening of Cl¯ [IPSPs] and/or K+ channels. • Indirect inhibition ---> Indirect inhibition • Pre-synaptic inhibition. • This happens when an inhibitory synaptic knob lie directly on the termination of a pre-synaptic excitatory fiber. • The inhibitory synaptic knob release a transmitter which inhibits the release of excitatory transmitter from the pre-synaptic fiber. • The transmitter released at the inhibitory knob is GABA. • The inhibition is produced by Cl¯ and K+. e.g. occurs in dorsal horm pain gating. • Fast neurotransmission: glutamate, GABA, glycine, acetylcholine • Metabolism and vesicular transport • Reuptake and degradation • Receptor systems • Pharmacology: agonists and antagonists • Synaptic integration • Neuromodulation: catecholamines, serotonin, histamine, neuropeptides • Overview of G-protein signaling • Metabolism and vesicular transport • Reuptake and degradation • Receptor systems, coupling, downstream targets • Pharmacology: agonists and antagonists 1. Structure and function of receptors Nerve Nerve Signal Messenger Receptor Response Nucleus Cell Cell 1. Structure and function of receptors Mechanism Induced fit Messenger Messenger Messenger Cell Membrane Receptor Receptor Cell Cell Receptor Cell message Message 1. Structure and function of receptors Chemical Messengers Neurotransmitters: Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve. Usually short lived and responsible for messages between individual cells Hormones: Chemicals released from cells or glands and which travel some distance to bind with receptors on target cells throughout the body • Chemical messengers ‘switch on’ receptors without undergoing a reaction • Control of ion channels • Receptor protein is part of an ion channel protein complex • Receptor binds a messenger leading to an induced fit • Ion channel is opened or closed • Ion channels are specific for specific ions (Na+, Ca2+, Cl-, K+) • Ions flow across cell membrane down concentration gradient • Polarises or depolarises nerve membranes • Activates or deactivates enzyme catalysed reactions within cell Control of ion channels Receptor Binding site Cell membrane Five glycoprotein subunits traversing cell membrane Messenger Induced fit ‘Gating’ (ion channel opens) Cationic ion channels for K+, Na+, Ca2+ (e.g. nicotinic) = excitatory Anionic ion channels for Cl- (e.g. GABAA) = inhibitory Cell membrane Figure 12.21 Neurotransmitter Functions Figure 12.21a Control of ion channels: MESSENGER ION CHANNEL (closed) Cell membrane Cell Ion channel RECEPTOR BINDING SITE Lock Gate Ion channel ION CHANNEL (open) Induced fit and opening of ion channel Cell membrane Cell membrane Cell Ion channel MESSENGER Ion channel Cell membrane Activation of signal proteins • Receptor binds a messenger leading to an induced fit • Opens a binding site for a signal protein (G-protein) • G-Protein binds, is destabilised then split messenger induced fit closed open G-protein split Figure 12.21 Neurotransmitter Functions Figure 12.21b Activation of signal proteins • G-Protein subunit activates membrane bound enzyme Binds to allosteric binding site Induced fit results in opening of active site • Intracellular reaction catalysed Enzyme Enzyme active site (closed) active site (open) Intracellular reaction Figure 12.21 Neurotransmitter Functions Figure 12.21c Activation of enzyme active site • Protein serves dual role - receptor plus enzyme • Receptor binds messenger leading to an induced fit • Protein changes shape and opens active site • Reaction catalysed within cell messenger messenger induced fit closed active site open intracellular reaction closed Neurotransmitters • There are dozens of different neurotransmitters (NT) in the neurons of the body. • NTs can be either excitatory or inhibitory • Each neuron generally synthesizes and releases a single type of neurotransmitter • The major neurotransmitters are indicated on the next slide. The classical neurotransmitters • Amines • Monoamines • catecholamines (dopamine, noradrenaline) • indoleamines (serotonin, melatonin) • Quaternary amines • acetylcholine • amino acids (glutamate, GABA) Cholinergic Synapses • Acetylcholine is a common transmitter. • Synapses that have acetylcholine transmitter are called cholinergic synapses. • Some neurones form more than 1 synapse. • This is an electron micrograph of synapses between nerve fibres and a neurone cell body. Acetylcholine ACh is a transmitter that is in a class by itself: • It is synthesized in terminals from acetyl CoA and choline by choline acetyltransferase. • It is packaged in vesicles in the axon terminals. • It can bind to two distinct receptor types: nicotinic and muscarinic. Nicotinic receptors are seen in the skeletal muscle synapse and at synapses within the CNS. Muscarinic receptors for ACh are also seen in the CNS and at parasympathetic synapses on target tissues. • After release, ACh is degraded by the enzyme acetylcholinesterase into acetate and choline. • The choline is taken back into the terminal by Na+-driven facilitated uptake. What happens at a cholinergic synapse? Stage 1 • An action potential arrives at presynaptic membrane. Voltage gated calcium channels in the presynaptic membrane open, calcium ions enter the presynaptic neurone. What happens at a cholinergic synapse? Stage 2 • Calcium ions cause synaptic vesicles to fuse with the presynaptic membrane, releasing acetylcholine into the synaptic cleft. What happens at a cholinergic synapse? Stage 3 • Acetylcholine diffuses cross the synaptic cleft and binds to specific neuroreceptor sites in the post synaptic membrane. What happens at a cholinergic synapse? Stage 4 • Sodium channels open. Sodium ions diffuse into the postsynaptic membrane causing depolarisation, which may initiate an action potential. What happens at a cholinergic synapse? Stage 5 • Acetylcholinesterase breaks down acetylcholine. The products diffuse back into the presynaptic neurone where acetycholine is resynthesised using ATP from the mitochondria. Amino acids: The workhorses of the neurotransmitter family Glutamate - the primary excitatory neurotransmitter in brains GABA (Gamma-amino-butyric-acid) - the primary inhibitory neurotransmitter The fabulous glutamate receptor Activation of NMDA receptor can cause changes in the numbers of AMPA receptors – a mechanism for learning? The fabulous GABA receptor Multiple binding sites GABA receptor binding sites GABA synthesis, release, reuptake, degradation 1. 2. 3. 4. 5. GABA is formed by removal of carboxyl group of glutamate, by the enzyme GAD GABA is packaged into synaptic vesicles by VIAAT and released by depolarization GABA may be taken up by nerve terminal by GAT proteins for repackaging into synaptic vesicles GABA may be taken up by glial cells, where it undergoes reconversion to glutamate (amine group is transferred to aketoglutarate, generating glutamate and succinic semialdehyde) Glutamate is transported back into nerve terminal, where it serves as precursor for new GABA synthesis a-ketoglutarate glutamate Major Neurotransmitters in the Body Neurotransmitter Role in the Body Acetylcholine A neurotransmitter used by the spinal cord neurons to control muscles and by many neurons in the brain to regulate memory. In most instances, acetylcholine is excitatory. Dopamine The neurotransmitter that produces feelings of pleasure when released by the brain reward system. Dopamine has multiple functions depending on where in the brain it acts. It is usually inhibitory. GABA (gamma-aminobutyric acid) The major inhibitory neurotransmitter in the brain. Glutamate The most common excitatory neurotransmitter in the brain. Glycine A neurotransmitter used mainly by neurons in the spinal cord. It probably always acts as an inhibitory neurotransmitter. Norepinephrine Norepinephrine acts as a neurotransmitter and a hormone. In the peripheral nervous system, it is part of the flight-or-flight response. In the brain, it acts as a neurotransmitter regulating normal brain processes. Norepinephrine is usually excitatory, but is inhibitory in a few brain areas. Serotonin A neurotransmitter involved in many functions including mood, appetite, and sensory perception. In the spinal cord, serotonin is inhibitory in pain pathways. NIH Publication No. 00-4871 Drugs Interfere with Neurotransmission • Drugs can affect synapses at a variety of sites and in a variety of ways, including: 1. Increasing number of impulses 2. Release NT from vesicles with or without impulses 3. Block reuptake or block receptors 4. Produce more or less NT 5. Prevent vesicles from releasing NT Drugs That Influence Neurotransmitters Change in Neurotransmission Effect on Neurotransmitter release or availability Drug that acts this way increase the number of impulses increased neurotransmitter release nicotine, alcohol, opiates release neurotransmitter from vesicles with or without impulses increased neurotransmitter release amphetamines methamphetamines release more neurotransmitter in response to an impulse increased neurotransmitter release nicotine block reuptake more neurotransmitter present in synaptic cleft cocaine amphetamine produce less neurotransmitter less neurotransmitter in synaptic cleft probably does not work this way prevent vesicles from releasing neurotransmitter less neurotransmitter released No drug example block receptor with another molecule no change in the amount of neurotransmitter released, or neurotransmitter cannot bind to its receptor on postsynaptic neuron LSD caffeine NIH Publication No. 00-4871 Ways that drugs can agonize • Stimulate release • receptor binding • inhibition of reuptake • inhibition of deactivation • promote synthesis Ways that drugs can antagonize • Block release • receptor blocker • prevent synthesis Drugs and the Synapse • Amphetamine stimulate dopamine synapses by increasing the release of dopamine from the presynaptic terminal. • Cocaine blocks the reuptake of dopamine, norepinephrine, and serotonin. • Methylphenidate (Ritalin) also blocks the reuptake of dopamine but in a more gradual and more controlled rate. Drugs and the Synapse • Nicotine stimulates one type of acetylcholine receptor known as the nicotinic receptor. • Nicotinic receptors are found in the central nervous system, the nerve-muscle junction of skeletal muscles and in the nucleus accumbens (facilitate dopamine release). Effect of nicotine and atropine Drugs and the Synapse • Ecstasy increases the release of dopamine at low doses that account for its stimulant properties. • Ecstasy increases the release of serotonin at higher doses accounting for its hallucinogenic properties. • Research indicates ecstasy use may contribute to higher incidences of anxiety and depression as well as memory loss and other cognitive deficits. Drugs and the Synapse • The brain produces peptides called endorphins. • Endorphin synapses may contribute to certain kinds of reinforcement by inhibiting the release of GABA indirectly. • Inhibiting GABA indirectly releases dopamine. • Endorphins attach to the same receptors to which opiates attach. How does alcohol affect synapses? • Alcohol has multiple effects on neurons. It alters neuron membranes, ion channels, enzymes, and receptors. • It binds directly to receptors for acetylcholine, serotonin, and gamma aminobutyric acid (GABA), and glutamate. • We will focus on GABA and its receptor. GABA and the GABA Receptor • GABA is a neurotransmitter that has an inhibitory effect on neurons. • When GABA attaches to its receptor on the postsynaptic membrane, it allows Cl- ions to pass into the neuron. • This hyperpolarizes the postsynaptic neuron to inhibit transmission of an impulse. Alcohol and the GABA Receptor • When alcohol enters the brain, it binds to GABA receptors and amplifies the hyperpolarization effect of GABA. • The neuron activity is further diminished • This accounts for some of the sedative affects of alcohol science.howstuffworks.com/ alcohol.htm Catecholamines Dopamine Subtantia nigra and Parkinson’s disease Mesocorticolimbic system and schizophrenia Receptor specificity Catecholamines Noradrenergic pathways in the brain -locus coeruleus Acetylcholine Cholinergic pathways in the brain -basal forebrain, neuromuscular junction • Acetylcholine is transmitted within cholinergic pathways that are concentrated mainly in specific regions of the brainstem and are thought to be involved in cognitive functions, especially memory. Severe damage to these pathways is the probable cause of Alzheimer’s disease. • There is a link between acetylcholine and Alzheimer's disease: There is something on the order of a 90% loss of acetylcholine in the brains of people suffering from Alzheimer's, which is a major cause of senility. Serotonin Serotonergic pathways in the brain -raphe, 15 subtypes, Prozac and depression • Low serotonin levels leads to an increased appetite for carbohydrates and trouble sleeping, which are also associated with depression and other emotional disorders. It has also been tied to migraines. • Low serotonin levels are also associated with decreased immune system function. • In addition to mood control, serotonin has been linked with a wide variety of functions, including the regulation of sleep, pain perception, body temperature, blood pressure and hormonal activity • Within the brain, serotonin is localized mainly in nerve pathways emerging from the raphe nuclei, a group of nuclei at the centre of the reticular formation in the Midbrain, pons and medulla. • These serotonergic pathways spread extensively throughout the brainstem , the cerebral cortex and the spinal cord . • People with too little GABA tend to suffer from anxiety disorders, and drugs like Valium work by enhancing the effects of GABA. Lots of other drugs influence GABA receptors, including alcohol and barbiturates. If GABA is lacking in certain parts of the brain, epilepsy results.