Neurotransmitters Week 14 PDF

Biochemistry of neurotransmitte rs Let us Review  What is a neurotransmitter? They are chemicals that communicate information throughout our brain and body. They can also affect mood, sleep, concentration, weight, and can cause adverse symptoms when they are out of bala...

Biochemistry of neurotransmitte rs Let us Review  What is a neurotransmitter? They are chemicals that communicate information throughout our brain and body. They can also affect mood, sleep, concentration, weight, and can cause adverse symptoms when they are out of balance. Neurotransmitters: Definition: Molecules that act as chemical signals between nerve cells Neurotransmitter, ✔ Synthesized within the neuron ✔ Stored in the nerve terminals (in synaptic vesicles) ✔ Released in response to an appropriate stimulus ✔ Able to bind to a receptor on post- synaptic membrane ✔ Locally inactivated & its action terminated  NEUROTRANSMISSION Steps involved in synaptic transmission (S-R-B-I) 1.S-synthesis and storage 2.R-release 3.B-binding 4.I-inactivation What are Synapse the junction between 2 cells where the impulse is transmitted from one cell to another 2 types of synapses Types of neurotransmitter Neuropeptides : neurohormones or neurotransmitters The neurotransmitters are stored in tiny sac- like structures called vesicles at the end of axons. When an impulse, or nerve signal, reaches the end of the axon, the vesicles release a neurotransmitter into the small space between the adjoining cells (synaptic cleft). Enzymes concerned with the synthesis of neurotransmitters are present both in the cell body and in the nerve ending. A portion of neurotransmitter is produced in the cell body and transported to the nerve ending. Neurotransmitters travel across the synapse and attach to specialized receptors on the receiving cell. This interaction can lead to different reactions in the receiving cell. It may become excited, triggering an action potential and transmitting an impulse, it may become inhibited and hyperpolarized, preventing the transmission of an impulse.  If neurotransmitters were allowed to operate over a long period of time, the results would be disastrous for the organism since there would be a constant overload of messages being sent. One way in which the problem is solved is through enzymes which break down the neurotransmitter very rapidly.  The knowledge about the neurotransmitters has led to the development of successful products for many brain disorders including epilepsy, schizophrenia, Parkinson’s disease, depression, anxiety disorders and migraine.  Neurotransmitter levels can be depleted many ways. Stress, poor diet, neurotoxins, genetic predisposition, drug (prescription and recreational), alcohol and caffeine usage can cause these levels to be out of optimal range.  Types of Neurotransmitters There are two kinds of neurotransmitters – INHIBITORY and EXCITATORY.  Small molecule neurotransmitters Postsynaptic Type Neurotransmitter effect Acetylcholine Excitatory Gamma Amino acids aminobutyric acid Inhibitory (GABA) Glycine Inhibitory Glutamate Excitatory Aspartate Excitatory Biogenic Dopamine Inhibitory amines Nor adrenaline Excitatory Serotonin Inhibitory Histamine Excitatory  Neuropeptides Neuropeptides are small protein like molecules (peptides used by neurons to communicate with each other (autocrine/paracrine) Neuronal signaling molecules ( not recycled back into the cell once secreted unlike glutamate , dopamine ,serotonin) Responsible for brain function Analgesia Food intake Learning and memory Metabolism, reproduction Social behaviors Neuropeptide neurotransmitters Neuropeptide neurotransmitters  CATECHOLAMINE S Contains catechol, composed of a phenyl ring with two adjacent hydroxyl side groups (found in all catecholamines)  Dopamine, norepinephrine, epinephrine Catecholamines: All synthesized from tyrosine Dopamine & norepinephrine → neurotransmitters Epinephrine → mainly as hormone → ‘fight or flight’ response From Tyrosi Phenylalani diet ne ne Tetrahydrobiopterin Tyrosine + O2 hydroxylase Dihydrobiopterin + H 2O Dihydroxy phenylalanine (DOPA) CO2 Aromatic a.a decarboxylase (PLP) Dopamine  Synthesis of Catecholamines 1. Phenylalanine from the liver is converted into tyrosine by phenylalanine hydroxylase. Tyrosine can also be supplied by the diet. 2. Hydroxylation of tyrosine by tyrosine hydroxylase → dihydroxyphenylalanine (DOPA). 3. The decarboxylation of DOPA by pyridoxal phosphate (DOPA decarboxylase) → dopamine 4. Dopamine is now stored in the synaptic vesicle where dopamine β-hydroxylase (DBH; this enzyme is only present within these storage vesicles) → norepinephrine. 5. Norepinephrine is now methylated by phenylethanolamine N-methyltransferase → epinephrine Storage of Catecholamines Transported into the vesicles via VMAT2 (vesicle monoamine transporter 2). Vesicular ATPase (V-ATPase) pumps protons into the vesicle to be exchanged for positively charged catecholamine. Serotonin and histamine can also be transported by VMAT2. Release of Catecholamines When an action potential hits the nerve terminal, Ca2+channels open → Ca2+ enters (the vesicles fuse with neuronal membrane) which then triggers the release of the content (neurotransmitter, ATP, chromogranins etc.) into the synaptic vesicle. Ready for exocytosis. They now diffuse across the synaptic cleft → they produce their specific response. Dopamine Found in : Brain and brainstem Substantia nigra (reward , addiction , movement) Hypothalamus (inhibits prolactin release) Use in treatment of: Schizophrenia, psychosis Parkinson’s disease Norepinephrine Found in: Brain: locus ceruleus , projecting to cortex , for arousal. Attention and anxiety ANS : sympathetic neurons (final product , postganglionic eurons Used in treatment of ADHD , Anxiety , cardiac failure COMT and MAO Parkinson’s disease What are some MAO inhibitor drugs? MAOIs were the first class of antidepressants to be developed. They fell out of favor because of concerns about interactions with certain foods and numerous drug interactions. MAOIs elevate the levels of norepinephrine, serotonin, and dopamine by inhibiting an enzyme called monoamine oxidase Regulation Tyrosine hydroxylase – Short term Inhibition by free cytosolic catecholamines Catecholamines compete with BH4 binding to enzyme Activation by depolarization – Tight binding to BH4 following phosphorylation by PKA, CAM kinases, PKC – Long-term (plus dopamine β-hyroxylase) – MAOI and you eat high-tyramine foods, tyramine can quickly reach dangerous levels. This can cause a serious spike in blood pressure and require emergency treatment. Pheochromocytoma: Rare tumor of adrenal medulla Secrete high levels of both epinephrine & norepinephrine ↑↑ plasma levels of catecholamines Causes hypertension, ↑ heart rate, may lead to stroke or heart failure ↑↑ degradation of catecholamines USED AS ↑↑ urinary excretion of VMA & DIAGNOSTIC TEST metanephrines ACETYLCHOLINE Acetylcholine was the first neurotransmitter to be discovered. It is responsible for much of the stimulation of muscles, including the muscles of the gastro-intestinal system. It is also found in sensory neurons and in the autonomic nervous system and has a part in scheduling REM Acetylcholine (Ach) Peripheral Nervous System Central Nervous System Acetylcholine is found in Acetylcholine is found in the the NMJ – Neuromuscular interneurons junction There is a cholinergic projection The AchR that is found here from the nucleus basalis Myenert are exclusively nicotinic to the forebrain neocortex that is Main Function: Stimulation associated with limbic structures of muscle fiber = AchR in the CNS are nicotinic contraction and muscarinic The degradation of this pathway is often associated with Alzheimer’s disease https://www.youtube.com/watch? v=MJECqcYJhmo 2 Types of receptor  Synthesis of acetylcholine Choline + acetylcoenzyme- A by choline acetyltransferase in cytoplasm Transported into and stored in vesicles. Removal: hydrolysis by acetylcholinesterase Degradation of acetylcholine No reuptake occurs Acetylcholinesterase Located in the post synaptic membrane Facilitates enzymatic inactivation of Ach Hydrolyzes Ach to form acetate and choline Acetate diffuses away, while choline is transported back to the presynaptic neuron by a choline carrie ACETYLCHOLINE 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 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) MYASTHENIA GRAVIS Autoantibodies formed against ACh receptors in neuromuscular junctions Bind to receptors & block access of ACh to them Damaged receptors endocytosed → reduce receptor number Inefficient transmission of nerve impulses to muscle Treated with drugs that inhibit acetylcholine esterase → increase concentration of ACh in the synaptic cleft → compensates for the reduced number of receptors MEDICAL APPLICATION - ACETYLCHOLINE Outside the brain, acetylcholine is the main neurotransmitter in the parasympathetic nervous system – the system that controls functions such as heart rate, digestion, secretion of saliva and bladder function. The plant poisons curare cause paralysis by blocking the acetylcholine receptor sites of muscle cells. The well-known poison botulin works by preventing the vesicles in the axon ending from releasing acetylcholine, causing paralysis.  SEROTONIN SEROTONIN is an inhibitory neurotransmitter – which means that it does not stimulate the brain. Adequate amounts of serotonin are necessary for a stable mood and to balance any excessive excitatory (stimulating) neurotransmitter firing in the brain. If you use stimulant medications or caffeine in your daily regimen – it can cause a depletion of serotonin over time.  Biologic effects of Serotonin GIT (enterochromaffin cells) 80% 🡪 regulates intestinal movements Brain 🡪 appetite, sexual behavior, and mood control Low level 🡪 depression Extremely high level 🡪 mania, reduced appetite and sexual behavior Pineal gland 🡪regulation of sleep Blood platelets 🡪 vasoconstrictor Serotonin Receptors….. Serotonin has more than a dozen receptors, and at least half of them have known clinical relevance. Only a few 5HT receptors are located on the serotonin neuron itself (5HT1A, 5HT1B/1D, 5HT2B), and their purpose is to regulate the presynaptic serotonin neuron directly. These same receptors can also be located —post-synaptically as can all known 5HT 1.) 5HT1A RECEPTORS : receptors. 2.) 5HT1B receptors: Are always inhibitory but located on GABA Located at the post synaptic 5HT1B and the interneurons in the prefrontal cortex, decreases presynaptic nerve terminals of other GABA release , net result excitatory effect on neurotransmitter, acts as heteroreceptor glutamate neurons Inhibitory and hence 5HT1B antagonists used. Also increases release of norepinephrine, histamine and dopamine and acetylcholine from 4.) 5HT3 receptors(excitatory) presynaptic terminals Located in brainstem chemoreceptor trigger zone Used in clinical practice,5HT1A agonist/partial outside BBB 3.) 5HT2A receptors agonist. Role in centrally mediated nausea and vomiting These are always excitatory In prefrontal cortex, located upon GABA interneurons, Depends on whether directly acts on the inhibit release of norepinephrine and acetylcholine glutamate neurons or via GABA interneurons RECIPROCAL NEUROTRANSMISSION: 5HT2A antagonists used in treatment of Tonic inhibition of glutamate output from prefrontal psychosis. cortex by Serotonin acting on 5HT3 receptors Hallucinogens have 5HT2A agonists Reduction in the excitatory feedback loop of properties. glutamate acting on the serotonin neurons at the leve of midbrain raphe nucleus  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. Can be found also in pineal gland These serotonergic pathways spread extensively throughout the brainstem , the cerebral An imbalance of serotonin in the brain is thought to contribute to depression, anxiety, poor mood, sexual dysfunction, OCD and stress The most common antidepressants are called selective serotonin reuptake inhibitors (SSRIs). They’re considered relatively safe and cause fewer side effects than other kinds of medications used to treat depression https://www.youtube.com/watch? app=desktop&v=bpgUHwjMeV4  Largest amount of serotonin is found in the intestinal mucosa. Although the CNS contains less than 2% of the total serotonin in the body, serotonin plays a very important role in a range of brain functions. It is synthesized from the amino acid tryptophan.  Synthesis of Tryptophan – precursor to serotonin Serotonin Once it enters the neurons, tryptophan hydroxylase adds the hydroxyl group and produces 5- hydroxytryptophan (5-HT) 5-HT is further decarboxylated by dopa decarboxylase to produce serotonin Serotonin is then stored in synaptic vesicles and docked at the nerve terminals, where it awaits an action potential Release of serotonin into the synaptic cleft activates serotonergic receptors in the post synaptic neurons  Low serotonin levels leads to an increased appetite for carbohydrates (starchy foods) and trouble sleeping, which are also associated with depression and other emotional disorders. It has also been tied to migraines, irritable bowel syndrome, and fibromyalgia. Low serotonin levels are also associated with decreased immune system  Inactivation and Degradation of Serotonin 1. Serotonin is inactivated by MAO (monoamine oxidase) 2. Oxidative deamination by MAO 🡪 5 hydroxyindole acetaldehyde 🡪 oxidized into 5 hydroxyindole acetic acid (found in uine) by aldehyde dehydrogenase Storage of Serotonin Vesicular ATPase proton pump via vesicular monoamine transporter 2 (VMAT 2) Reuptake: Serotonin Transporter (SERT) Carcinoid syndrome: Serotonin producing tumors arising from enterochromaffin cells of GI tract, may metastasize to the liver or lungs Increased plasma level of serotonin Attacks of flushing, ↑ heart rate, abdominal pain & diarrhea Increased urinary excretion of 5-HIAA (diagnostic test) 56 Melatonin Serotonin is synthesized in the pineal gland and serves as a precursor for the synthesis of melatonin which is a neurohormone involved in regulating: Sleep patterns Seasonal and circadian rythyms Dark-light cycle Synthesis of Melatonin Serotonin (precursor) 1. Acetylation of the amine group by N-acetyl transferase leading to N-acetyl serotonin 2. Methylation of the OH group by 5-hydroxyindole🡪 O- methytransferase catalyzing the transfer of a methyl group by S-adenosylmethionin to obtain acetyl-5 methoxytryptamine or melatonin  Gamma amino butyric acid (GABA) Gamma amino butyric acid(GABA) is the major inhibitory neurotransmitter that is often referred to as “nature’s VALIUM-like substance”. When GABA is out of range (high or low excretion values), it is likely that an excitatory neurotransmitter is firing too often in the brain. GABA will be sent out to attempt to balance this stimulating over- GABA GABA is present in high concentrations (millimolar) in many brain regions. GABA is derived from glucose, which is transaminated in the Kreb’s cycle to glutamine and then converted to GABA by the enzyme, glutamic acid decarboxylase. GABA shunt The GABA shunt is a closed-loop process with the dual purpose of producing and conserving the supply of GABA. GABA is converted back to glutamate via GABA hunt (Catalyzed by enzyme GABA-T, or α-oxoglutarate transaminase in the presence of αketoglutarate to form 2 molecules Glutamate & Succinic semialdehyde (SSA))  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.  Storage Vesicular Inhibitory Amino Acid Transporter (VIAAT) Vesicular GABA transporter (VGAT) Release and Binding GABA is released into the presynaptic cleft after depolarization 2 receptors: GABA A - ligand-gated ion channels GABA B - G protein- coupled receptors Dementia 1.) Accumulation of amyloid plaques, tau tangles and lewy bodies and damage caused by strokes, may destroy some glutamatergic pyramidal neurons and GABA interneurons. 2) Loss of GABA inhibition upset the balance. 3) Excessive glutamate release hyperactivity of mesolimbic dopamine pathway.(Delusion and Auditory hallucinations , Excessive glutamate in visual cortex : visual hallucinations). Glycine Biologic Effect Most important inhibitory neurotransmitter in the spinal cord, lower brainstem, and retina Function as coagonist at the NMDA glutamate receptor 🡪 glycine promotes the actions of glutamate 🡪 glycine serves both inhibitory and excitatory Reuptake - Released glycine is taken up by neurons by an active sodium-dependent functions within the CNS mechanism involving specific membrane transporters (glycine transporter 2). Synthesis & Storage Reaction is catalyzed by serine hydroxymethyltransferase (SHMT) Transfer of the hydroxymethyl group from serine→tetrahydrofolate (THF), producing glycine. Stored in neuronal synaptic vesicles by vesicular inhibitory amino acid transmitter (VIAAT).  Three pathways of degradation for glycine Glycine Cleavage System (GCS): Involves conversion of glycine into serine and ammonia. Important for folate metabolism and one-carbon unit transfer. Conversion to Glyoxylate: Glycine can be converted to glyoxylate via several enzymatic reactions. Glyoxylate is a precursor for various metabolites, including oxalate. Transamination: Glycine can participate in transamination reactions, transferring its amino group to other compounds. For example, it can donate its amino group to pyruvate, forming alanine in the process. HISTAMINE Amino acid Histidine is the precursor of an important neurotransmitter histamine. Histamine is present in venom and other stinging secretions. Histidine is decarboxylized by the Produced by mast cells enzyme histidine decarboxylase and by certain neuronal (requires pyridoxal phosphate) to fibers within the brain histamine Potent local mediator of Histamine it does not penetrate the blood—brain barrier and, hence, must be synthesized. Pyridoxal phosphate X Neuron Astrocytes Histamine Histamine is a biogenic amine involved in local immune responses Regulate physiological function in the gut Act as a neurotransmitter. Triggers the inflammatory response. Storage- Vesicular ATPase proton pump via vesicular monoamine transporter 2 (VMAT 2) Biologic Effects of Histamine Histamine As part of an immune response to foreign pathogens, histamine is found in bound form in granules in basophils and mast cells found in nearby connective tissues. The bound form is inactive, but stimuli causes its release from these granules. Inactivation and degradation of Histamine Histamine, unlike other neurotransmitters, is not recycled into the presynaptic terminal. Astrocytes, however, have a specific high-affinity uptake system for histamine and may be the major sites of the inactivation and degradation of histamine. Patients with allergic reaction cannot degrade histamine because they have low activity of diamineoxidase. 1st step: methylation. Histamine methyltransferase transfers a methyl group from S-adenosylmethionine (SAM) to a nitrogen ring of histamine to form methylhistamine 2nd step: oxidation. Oxidation by MAO-B, followed by an additional oxidation step. In the peripheral tissues, histamine undergoes deamination by diamine oxidase followed by oxidation to a carboxylic acid. Histamine Storage and release- Mast cells or basophils. Most histamine in the body is stored in granules in mast cells or in white blood cells called basophils. Mast cells are especially numerous at sites of potential injury - the nose, mouth, and feet, internal body surfaces, and blood vessels. Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach. Release of histamine Aspartate Aspartate is an excitatory Other uses of Aspartate neurotransmitter in the central Protein Building: Essential nervous system. It is involved amino acid for protein synthesis. in transmitting nerve signals Urea Cycle: Integral in between neurons and plays a detoxifying the body by role in cognitive functions and converting ammonia into urea. neural communication. Krebs Cycle: Participates as an intermediate in the citric acid cycle for energy production. Nucleotide Biosynthesis: A precursor for DNA and RNA nucleotides. Gluconeogenesis: Converts to oxaloacetate for glucose generation. Synthesis of ASPARTATE transamination reaction can also be derived from catalyzed by aspartate asparagine through the aminotransferase, AST action of asparaginase Receptors and Degradation of Aspartate Receptors Degradation of Inotropic (same with Aspartate glutamate): N-methyl-d-aspartate (NMDA) Α-amino-3-hydroxy-5- methyl-4- isoxazolepropionic acid (AMPA) Kainit Glutamate Found everywhere in CNS: Excites the cerebral cortex , spinal cord , brainstem , hippocampus , cerebellum Nonessential amino acids Do not cross BBB must be synthesized in neurons Main synthetic compartments neurons glial cells excitatory neurotransmitters. Function of Glutamate Functions as major excitatory NT within the CNS, leading to depolarization of neurons Glutamate plays a role in learning and memory processes, as well as motor function Amyotrophic lateral sclerosis (ALS)/Lou Gehrig’s disease - characterized by degeneration of the motor neurons in the anterior horn of the spinal cord, brainstem, and cerebral cortex. Excitotoxicity – neuronal death by prolonged stimulation of neurons by excitatory amino acids Excess glutamate can overstimulate the brain and cause seizures  Storage and Release Glutamate is stored in the synaptic vesicle via Vesicular Glutamate Transporter/VGluT, and subsequently released by exocytosis. Receptors-Release is Ca2+ dependent Synthesis of glutamate Deamination of glutamine Glu o The intermediate alpha Dehydro ketoglutarate (α KG) from glucose transaminase 1 metabolism (via TCA pathway) can be α-KG transformed into glutamate by 2 Dehydrogenation – transfer of free glutaminase Glutamine ammonia to α KG to form glutamate synthetase Transamination – ammonia/amino group from any amino amino acid to form 3 Glutamate Removal GABA excitatory amino acid carrier-1 (EAAC1) glutamate transporter-1 (GLT-1) and glutamate—aspartate transporter (GLAST) Reuptake and Degradation of Glutamate Nerve terminals and glial cells reuptake the glutamate released from the nerve terminals. In the glia, glutamate is converted into glutamine-by-glutamine synthetase. Glutamine is inactive in a sense that it cannot activate glutamate receptors It is then released from the glial cell into the extracellular fluid where nerve terminals take up glutamine (glutamine 🡪 glutamate; glutamate 🡪 glutamine cycle)  The NMDA Glutamate Hypofunction Hypothesis of Psychosis IN PRESENCE OF HYPOFUNCTIONAL NMDA GLUTAMATE RECEPTOR :- (1)Glutamate is released from an intracortical pyramidal neuron. NMDA receptor that it would normally bind to at the GABA interneurons is hypofunctional, preventing glutamate from exerting its effects at the receptor. This could be due to Neurodevelopmental or drug toxicity resulting from Abnormalities ketamine or phencyclidine abuse This prevents GABA release from the interneuron; thus, binding of GABA to GABA receptors on the axon of another glutamate neuron does not occur. The pyramidal neuron is no longer inhibited. Instead, it is disinhibited  Activity of the day Exploring Neurotransmitters and Mental Illness Through a Mind Mapping Exercise Team capybara - Schizophrenia Team kitty - Depression Mind Mapping Activity (Same groupmates) Encourage students to use colors, symbols, and drawings to visually represent the concepts and make the mind map engaging. Students should connect neurotransmitters to specific symptoms or aspects of the mental illness (e.g., "Low Serotonin -> Mood Regulation -> Depressed Mood"). Emphasize the interconnectedness of neurotransmitters and how they contribute to the overall picture of the mental illness./ physical health  https://www.youtube.com/watch?v=KMVJMMwB4vE&ab_ channel=MedicineTechnology-SchoolofMedicine-JU https://judoctor2011.files.wordpress.com/2014/02/bioch emistry_of_neurotransmitters_2014.pdf https://www.youtube.com/watch?v=ijLdLjl_wTQ&ab_cha nnel=MedLecturesMadeEasy