Chapter 6: Neurotransmitter Systems
Chapter 6: Neurotransmitter Systems NEUROSC 3000 - 020
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NEUROSC 3000 - 020
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This 21 page Class Notes was uploaded by Victoria Gonzalez on Wednesday November 4, 2015. The Class Notes belongs to NEUROSC 3000 - 020 at Ohio State University taught by Robert Boyd in Summer 2015. Since its upload, it has received 19 views. For similar materials see Introduction to Neuroscience in Neuroscience at Ohio State University.
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Date Created: 11/04/15
1 Chapter 6: Neurotransmitter Systems Victoria Gonzalez Learning Objectives: Understand how neurotransmitters are identified and localized Know how the major neurotransmitters are synthesized Understand the structure and function of the major groups of ligandgated receptors Understand the structure and function of Gprotein coupled receptors 1. Introduction a. The first neurotransmitter identified was acetylcholine (Otto Loewi) b. The term cholinergic was introduced to describe cells that produce and release acetylcholine (Henry Dale) c. Noradrenergic: neurons that use the amine neurotransmitter norepinephrine (Henry Dale) d. Glutamatergic: synapses that use glutamate e. GABAergic: synapses that use GABA f. Peptigergic: synapses that use peptides 2. Studying neurotransmitter systems a. Criteria for being considered a neurotransmitter: i. Molecule must be synthesized and stored in the presynaptic neuron ii. The molecule must be released by the presynaptic axon terminal in response to stimulation iii. When experimentally applied, the molecule must produce a response in the postsynaptic cell mimicking the response produced by the release of neurotransmitter from the presynaptic neuron b. To study: molecule must be synthesized & stored in presynaptic neuron i. Immunocytochemistry: make antibodies to specific transmitters or enzymes which synthesize the transmitter 1. Used to localize particular molecules to particular cells 2. Neurotransmitter is injected under skin or into bloodstream 3. An immune response is stimulated—antibodies are made and tagged with fluorescent /radioactive markers 4. Antibodies bind to the antigen (neurotransmitter or enzymes that make the neurotransmitter) 5. Antibody tags light up parts of the brain where the neurotransmitter is present 6. Best antibodies: bind tightly to antigen and not to other chemicals in the brain a. Antibodies for enzymes that make neurotransmitters are better than for the neurotransmitter itself 2 7. To be a neurotransmitter candidate, the neurotransmitter and its synthesizing enzyme must be contained in the same neuron ii. In situ hybridization: confirms that a cell synthesizes a particular protein or peptide 1. If a sequence of nucleic acids is known for a particular protein, a complementary strand of mRNA is synthesized in a lab 2. The lab synthesized mRNA probe is labeled with a radioactive marker; it sticks to the complementary strand of mRNA 3. To see the cells with the markers, brain tissue is laid on a sheet of special film sensitive to radioactive emissions (autoradiography) 4. Radioactive cells are visible as clysters of white dots c. To study: the molecule must be released by the presynaptic axon terminal upon stimulation i. Transmitter release is difficult to study; we cannot be sure that the transmitter was released from synaptic terminals; they might have been released as a secondary consequence of synaptic activation ii. Fluid near the axons or cells can be tested for a substance after the neuron has been stimulated (Loewi and Dale) iii. CNS synapses using different neurotransmitters are proximally close; a single population of synapses cannot be stimulated iv. Brain slices are kept alive in vitro and soaked in a solution of high + 2+ K and Ca + 1. High K concentration causes depolarization (action potential) and stimulates release 2. High Ca concentrations expel neurotransmitters from presynaptic axons v. Optogenetics: used to control signaling in individual neurons 1. Specific neurons are excited in the cell to see if neurotransmitters are released d. 3 e. To study: when applied experimentally, the molecule must produce a response in the postsynaptic cell that mimics the response produced by the release of neurotransmitter from the presynaptic neuron i. Microiontophoresis: assesses the postsynaptic actions of a transmitter 1. Neurotransmitter is dissolved into solution 2. Solution is injected into cell axon before the postsynaptic neuron 3. To administer very small amounts, an electrical current is run through the micropipette 4. A microelectrode in the postsynaptic neuron can be used to measure the effects of the transmitter on the membrane potential 5. A neurotransmitter must mimic the effects of the transmitter released at the synapse f. Studying neurotransmitter receptors i. Each neurotransmitter can bind to various receptor subtypes ii. Two different neurotransmitters (ex: Ach, GABA) can’t bind to the same receptor iii. Neuropharmacology: uses agonists and antagonists to classify receptor subtypes iv. Agonist: compound that mimics action of neurotransmitter and stimulates receptor v. Antagonists: blocks action of normal neurotransmitter and inhibits receptors vi. Skeletal and heart muscle respond differently to various cholinergic drugs 1. Nicotine is an agonist in skeletal muscles; has no effect on heart 2. Muscarine is an agonist in the heart; has no effect on skeletal muscle 3. Acetylcholine and muscarine slow heart rate vii. Glutamate receptors: AMPA, NMDA, Kainate 1. Glutamate neurotransmitter binds at all three receptor subtypes 2. Each agonist only binds to their respective receptor a. AMPA only binds to AMPA receptor b. NMDA only binds to NMDA receptor c. Kainate only binds to kainate receptor g. 4 h. Ligandbinding methods i. Ligand: any chemical compound that binds to a specific site on a receptor ii. Lingbinding method: use labeled ligands to bind specifically to receptors 1. Important for mapping anatomical distribution of neurotransmitter receptors in the brain iii. Ligand can be the neurotransmitter, agonist, antagonist iv. Ligands can be toxins or components of venom (snails, snakes, spiders) i. Molecular analysis i. Cloning of many receptor cDNAs ii. Each receptor has five subunits which can be made up of a variety of polypeptides iii. Diversity of subtypes are larger than expected because of binding and pharmacology 3. Neurotransmitter chemistry a. Most neurotransmitters are: i. Amino acids ii. Amines made from amino acids iii. Peptides made from amino acids b. Dale’s principle: a neuron only has one neurotransmitter i. Neurons containing peptides violate this idea because they release a peptide and either an amino acid or an amine ii. Now we know that there are neurons with dual transmitters c. Cotransmitters: two or more transmitters that are released from one nerve terminal i. But most neurons release a single amino acid or amine neurotransmitter 4. Neurotransmitter transport a. Transport uses ATP (transmembrane gradients of NA or H ) to create higher concentrations b. There are two types of transport c. Neuronal membrane transporter: shuttles transmitter from extracellular fluid and synaptic cleft and concentrated it up to 10,000 times higher within the cytosol of the presynaptic terminal i. Cotransport mechanism is used: 2 sodium ions are carried across the membrane with one transmitter molecule d. Vesicular transporter: crams transmitter into vesicles at concentrations 100,000 times higher than in the cytosol i. Countertransport mechanism is used: a transmitter is traded for two protons from inside the vesicle 5 5. Cholinergic neurons: acetylcholine a. Acetylcholine is the neurotransmitter at neuromuscular junctions i. Synthesized by all motor neurons in spinal cord and brain stem b. Choline acetyltransferase (ChAT) is required for synthesis i. ChAT is only in cholinergic cells so it is a good marker for cells that use acetylcholine c. Two major groups of cholinergic neurons in the brain d. Basal forebrain neurons: learning, memory i. Degraded during Alzheimer’s e. Dorsolateral pontine tegmental constellation: excitability of sensory relay systems f. In many circuits in the autonomic (involuntary) nervous system g. Choline is taken up from extracellular fluid by a specific transporter h. Uptake is the ratelimiting step, i. Alheimer’s treatments involve in+reasingcholine levels ii. Requires the cotransport of Na and Cl i. Once in the presynaptic cell, choline and acetyl CoA combine to make acetylcholine which is then packaged in a vesicle i. Packaged by VAChT: vesicular acetylcholine transporter 1. Protons enter the vesicle against their concentration gradient; using ATP 2. Acetylcholine is countertransported; two protons leave the cell and one acetylcholine molecule enters 6 j. Acetylcholine is released and binds to acetylcholine receptors k. acetlycholinesterase (AChE) degrades acetylcholine into choline and acetic acid in the synaptic cleft (and on axon membranes) i. 5,000 / second; AChE has one of the fastest catalytic rates ii. Made by some cholinergic and some noncholinergic neurons 1. This enzyme is not a good marker for cholinergic synapses (ChAT is) iii. Nerve gas and some insecticides block AChE 1. Inhibition of AChE prevents the breakdown of ACh 6. Catecholaminergic neurons a. Catecholamine neurotransmitters all have tyrosine as a precursor i. Dopamine (DA) ii. Norepinephrine (NE) iii. Epinephrine (adrenaline) b. Involved in mood, movement, attention, and autonomic functions 7 c. All contain tyrosine hydroxylase (TH), catalyzes the first step; converts tyrosine into dopa i. Good marker for tracking catecholaminergic neurons ii. Rate limiting step iii. Uses endproduct inhibition 1. Increa2+d catecholamine build up in cytosol inhibits TH iv. Increased Ca in the presynaptic cell increases TH activity (because a lot of catecholamines have been released) 8 d. Dopaminergic neurons i. Dopa is converted into dopamine by dopa decarboxylase 1. Dopa decarboxylase is abundant; amount of dopamine synthesized depends on the amount of dopa available ii. Parkinson’s disease: dopaminergic neurons degrade and die 1. Treatment: administer dopa to increase the amount of dopamine available for release a. Can’t administer dopamine because it cannot cross the bloodbrain barrier e. Norepinephrine (NE) neurons i. Norepinephrine neurons contain dopamine Bhydroxylase (DBH) which converts dopamine to norepinephrine 1. DBH is found in synaptic vesicles; in noradrenergic axon terminals, dopamine is transported from the cytosol to the synaptic vesicles to be made into norepinephrine ii. Norepinephrine has the most diffuse distribution iii. Activated by new, nonpainful stimuli iv. Modulate attention, feeding behaviour, sleep, mood, arousal, learning, memory, pain, brain metabolism v. Neurons are in the locus coeruleus and project to cortex, hypothalamus and hippocampus f. Epinephrine (adrenaline) i. Adrenergic neurons contain phentolamine Nmethyl transferase (PNMT) 1. PNMT is found in the cytosol 2. Norepinephrine must be made in a vesicle and then released into the cytosol to be made into epinephrine 3. Epinephrine is transported back into vesicle for release ii. Epinephrine also acts as a hormone when released into the bloodstream by the adrenal glands iii. Major groups of neurons are found in the medulla iv. Present at lower levels than other catecholamines v. Present in fewer neurons, function in CNS is not known g. Catecholaminergic neurons i. Are not degraded in the synaptic cleft ii. They are transported back into the presynaptic neuron by specific + Na dependent transporters 1. Amphetamines and cocaine block the reuptake increasing the binding of neurotransmitters with post synaptic receptors iii. After reuptake catecholamines can be: 1. Reloaded back into vesicles 9 iv. Destroyed by monoamine oxidase (MAO) in the outermembrane of the mitochondria v. Antibodies to enzymes in the pathways are used to identify catecholaminergic neurons 10 7. Serotonergic neurons a. The amine neurotransmitter serotonin is also called 5hydroxytryptamine (5HT) b. It is derived from the amino acid tryptophan i. Tryptophan comes into the body through diet and is carried into the brain by the blood c. Serotonergic neurons are few in number but have a widespread distribution and are therefore widespread in function i. Controls mood, emotional behaviour, and sleep ii. Neurons are found in the pons and the upper brainstem iii. Projections are to the forebrain iv. Raphe nucleus neurons regulate pain signaling d. Serotonin is a precursor to melatonin in the pineal gland e. Synthesis: i. Tryptophan is converted to 5hydroxytryptophan (5HTP) intermediate by the enzyme tryptophan hydroxylase ii. 5HTP is then converted to 5HT (serotonin) by the enzyme 5 HTP decarboxylase iii. Synthesis is limited by the amount of tryptophan in extracellular fluids f. Serotonin reuptakes by a specific transporter i. Antidepressants (Prozac) and antianxiety drugs inhibit serotonin reuptake causing an increase in 5HT receptors ii. Ecstasy on the other hand, stimulates serotonin release to produce sensory enhancement and empathy 1. Long term use may destroy serotonergic projections 2. Short term use may produce tachycardia, hyperthermia, and dehydration g. After reuptake serotonin is: i. Repackaged into vesicles for reuse 11 ii. Degraded by MAO 12 8. Amino acid neurotransmitters a. Glutamate (Glu), Glycine (Gly), Gammaaminobutyric acid (GABA) b. Glutamate and glycine are amino acids used to make proteins i. They are synthesized from glucose ii. They are found in every cell but glutamatergic cells have a higher concentration of them (23x higher) c. Glutamate: the major excitatory neurotransmitter (half of all synapses in the brain) i. Involved in learning, memory, and motor functions ii. Implicated in ALS, long term depression, long term potentiation iii. Excitotoxicity (nerve cells are killed by excessive stimulation) by glutamate during a stroke may play a role in Alzheimer’s iv. Glutamate is taken up by glial cells and recycled 1. Glial cells turn glutamate back into glutamine 2. The neuron reuptakes glutamine and converts it to glutamate again d. GABA is synthesized by neurons that use it as a neurotransmitter i. GABA: major synaptic inhibitor ii. GABAergic neurons are distributed widely 1. Mostly present as interneurons; can be in purkinje cells: projection neurons (not in peripherals) iii. Glutamate is made into GABA by an enzyme, glutamic acid decarboxylase (GAD) 1. GAD is a good marker for GABAergic neurons 2. GAD is not present in glutamatergic neurons or glia iv. GABA is packaged into synaptic vesicles by a vesicular inhibitory amino acid transporter (VIATT) v. Metabolized by transporters (GATs) into neurons and glia 1. Broken down into the mitochondria vi. GABA signaling deficits: Huntington’s, Parkinson’s, schizophrenia vii. Barbiturates: alter GABA receptors (used to treat epilepsy) 13 e. Glycine: inhibitory neurotransmitter i. GABA concentrated in the CNS cortex; glycine is everywhere 1. Half of inhibitory synapses in the spinal cord ii. Synthesized from serine by serine hydroxymethyltransferase iii. Loaded into vesicles by a vesicular inhibitory amino acid transporter iv. Removed from cleft by plasma membrane glycine transporters 9. ATP: an excitatory neurotransmitter a. Usually packed in vesicles with other neurotransmitters (cotransmitter) b. ATP and adenosine receptors are widespread c. ATP binds to purinergic receptors i. Ligand gated (Gprotein coupled) receptors and transmitter gated 10. Endocannabinoids: neurotransmitters that use retrograde signaling: communication from post synaptic neurons to presynaptic terminals a. Inhibit presynaptic Ca channels to prevent release of neurotransmitters i. Firing of action potentials on postsynaptic neurons cause voltage gated calcium channels to open ii. Calcium enters the cell and stimulates the synthesis of endocannabinoids from lipids b. Endocannabinoids are not packaged in vesicles; made rapidly on demand i. They are small and membrane permeable c. Bind to CB1 receptors (Gprotein coupled) on presynaptic terminals 11. Nitric oxide (NO) a. Synthesized from amino acid arginine b. Released by postsynaptic neurons (retrograde signaling) c. Permeable to membranes d. Regulates blood flow when not being used as a neurotransmitter 14 12. Transmittergated channels a. Structure i. Most transmittergated channels have a structure similar to nicotinic acetylcholine receptors (nAChR) from skeletal muscles ii. Contain 5 subunits made up of the four possible types: α, β, γ, δ iii. ACh binding sites require α subunit, where the ACh binding sites are 1. It requires two ACh molecules to bind to the two α subunits in order to open the channel iv. Each of the 5 subunits is made up of 4 alpha helical trans membrane regions v. Glutamate receptors are an exception: made from four subunits that do not span the membrane vi. There are unique differences that account for ligand binding, Na, K, Ca, Cl, etc. permeability b. Amino acid gated channels i. Amino acidgated channels mediate most of the fast synaptic transmissions in the CNS ii. Involved in many sensory systems, memory and diseases iii. The pharmacology of their binding sites describes which transmitters affect them and how drugs interact with them iv. The kinetics of transmitter binding and channel gating determine the duration of their effects v. The selectivity of the ion channels determines whether they produce excitation or inhibition, and whether calcium enters the cell in significant amounts 15 vi. The conductance of open channels helps determine the magnitude of their effects 16 vii. Glutamategated channels: there are three types + + 1. AMPA: permeable to Na and K a. Mediate excitatory transmissions + b. Activation causes depolarization because Na entry is more than K exiting c. These coexist with NMDA receptors 2. NMDA: permeable to Ca , Na and K + a. Inward current is voltagedependent: the channel will open when the cell is depolarized (by AMPA) b. When the channels open, Ca and Na enter the cell + and K leaves 3. Kainate viii. GABAgated channels 1. GABA is responsible for inhibition in the CNS; glycine mediates everywhere 2. GABA , GABA , GABAB C a. A and C are ionotropic: inhibitory; gate Cl b. B is metabotropic 3. GABA anA glycine receptors open a gate for Cl a. Their structures are similar to nAChR b. α binding subunits, β nonbinding 4. GABA reAeptors have several sites where chemicals can modulate its function a. Benzodiazepines increase frequency of opening b. Barbituates increase the time the channel is open ix. Glycinegated channels 1. Ligand gated Cl channels 2. Similar in structure to GABA reAeptors 3. Cysloop family member 4. Strychnine is an antagonist 17 13. Gprotein coupled receptors a. Transmission at Gprotein coupled receptors requires 3 steps: i. Neurotransmitter binds to the receptor protein ii. Gprotein is activated iii. The effector systems are activated b. Structure of Gcoupled protein receptors i. Consist of one polypeptide with 7 transmembrane alpha helices ii. 2 of the extracellular loops form binding sites for the ligands 1. G proteins bind to some of the intracellular loops iii. 100 different G protein linked receptors are known iv. Structural variations determine which Gproteins and which effector systems are activated in response to transmitter binding 18 c. G proteins: guanosine triphosphate (GTP) binding proteins i. There are about 20 different kinds of G proteins ii. Three subunits: α, β, γ iii. Basic mode of operation: 1. When inactive, the α subunit of the G protein binds GDP 2. When activated by a G protein coupled receptor, the GDP is exchanged for GTP 3. The activated G protein splits into G αnd G aβγ they both activate effector proteins 4. The G subunit slowly removes one phosphate from GTP α converting it back to GDP to terminate the cycle iv. G sis stimulatory, G i inhibitory (can close and open channels) d. Shortcut pathway: fastest g protein coupled system (30100 msec) i. G protein binds to ion channels causing them to open or close ii. Process is localized: the G protein does not move far e. Second messenger cascades: requires multiple steps i. G protein activates enzyme which activates downstream enzymes ii. Kinases and phosphates are involved in many cascades 19 20 f. Activated G proteins can sometimes stimulate multiple pathways g. Different G proteins can have opposite effects i. Processes are regulated by stimulation (G ) snd inhibition (G) i h. Signal cascades i. Slow process but has its advantages ii. Amplification: the amplification of one g protein coupled receptor can lead to the activation of many ion channels 1. A neurotransmitter can bind to one receptor and activate many g proteins iii. Provide many sites for further regulation iv. Longer range of signaling: cascades; cascades can then interact with other cascades v. Long lasting effects: memories vi. Kinases and phosphates are involved in many cascades 14. Divergence and convergence in neurotransmitter system a. Divergence: the ability of one transmitter to activate more than one subtype of receptor and cause more than one type of postsynaptic response b. Convergence: multiple transmitters each activating their own receptor type converge to influence the same effector system 21
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