SYNAPTIC TRANSMISSION AND NEUROTRANSMITTERS trans final 2.pdf

NEUROSCIENCE 15" SEM 2021 poppy&lucy SYNAPTIC TRANSMISSION AND...

NEUROSCIENCE 15" SEM 2021 poppy&lucy SYNAPTIC TRANSMISSION AND NEUROTRANSMITTERS PROPERTIES OF ELECTRICAL AND CHEMICAL SYNAPSE SYNAPSE Po ELECTRICAL ferro. e Electrical signals must pass across the IONOTROPIC. METABOTROPIC. specialized gap region between two apposing AGONIST NONE e.g. ACh e.g. ACh cell membranes that is called a synapse. MEMBRANE Connexon Receptor/channel Receptor/G The process underlying this cell-to-cell transfer PROTEIN protein of electrical signals is termed synaptic SPEED OF Instantaneous 1 ms delay Seconds to minutes. TRANSMISSIO transmission. N Electrical synapses provide direct electrical continuity between cells by means of gap Electrical synapse junction True structural connection formed by connexon Chemical synapses link two cells together by a channels of gap junctions that link the chemical neurotransmitter that is released cytoplasm of two cells | (elactrotonic current) from one cell and diffuses to another. The interface between the motor neuron and the muscle cell is called the neuromuscular junction. Synapse | Presynaptic axon axon synaptic vesicles Neurotransmitter Y Synaptic 4} Synaptic Cleft Vesicles Connexon Small ions \ \! de @% Postsynaptic een channels and molecules ry OT @@ ° Ys veg = Postsynaptic Cell-cell aap iunction neurotransmitter Cell 7 dendrites i “receptor Gap-junction channel A Current pathways at electrical synapses B Current pathways at chemical synapses Specialized region of contact between two neurons at an electrical synapse Consists of a pair of connexons (hemichannels)- one in the pre- and the other in the postsynaptic cell membrane Form a continuous bridge that provides a direct Prasynapitic Presynaptic Pastsynaptic communication path between the two cells Table 8-1 Distinguishing Properties of Electrical and Chemical Synapses 3 Each connexon is composed of six identical subunits Distance Cytoplasmic.. between cantinaly called connexins. Each subunit has an N- and C- Typeof preand _ between pre> postsynaptic cell and postsynaptic Ultrastructural Agent of Synaptic ) ey Direction of terminus with four interposed alpha-helixes. synapse membranes cells components transmission delay transmission Modulatory factors: that control their opening and Electrical = 4nm Yes Gap-junction Ton current Virtually Usually Ps Ps 2+ channels absent bidirectional closing Cytoplasmic pH, Ca D released Chemical 2040 nm No Presynaptic Chemical Significant: Unidirectional neurotransmitters vesicles and transmitter at least 0.3 ms, active zones; usually postsynaptic 1-5 ms receptors or longer NEUROSCIENCE 15" SEM 2021 poppy&lucy Instantaneous signal transmission because current passes CHEMICAL SYNAPSE directly from one cell to another The presynaptic terminal must be big enough for its membrane to contain many ion channels and the postsynaptic cell must be small. to generate a large current The change in potential of the postsynaptic cell is directly related to the size and shape of the change in potential of the presynaptic cell. Electrotonic Most electrical synapses can transmit both transmission depolarizing and hyperpolarizing currents Signal transmission is similar to the passive propagation of subthreshold electrical signals along axons PROCESS OF CHEMICAL TRANSMISSION Rectifying Gap junctions that have voltage-dependent Step 1: Neurotransmitter molecules are packaged into synapses gates that permit them to conduct depolarizing synaptic vesicles. Specific transport proteins in the current in only one direction vesicle membrane use the energy of an H+ gradient to energize uptake of the neurotransmitter in the vesicle. Step 2: An action potential, which involves voltage- Role of Gap Junctions in Glial Function gated Na+ and K+ channels, arrives at the presynaptic nerve terminal Astrocytes in the brain are connected to each other through Step 3: Depolarization opens voltage-gated Ca2+ gap junctions forming a glial cell network channels, which allows Ca2+ to enter the presynaptic Gap junctions also enhance communication in the Schwann terminal. cells in the PNS. These gap junctions may help to hold the Step 4: The increase in intracellular Ca2+ concentration layers of myelin together and promote the passage of small ({[Ca2+]i) triggers the fusion of synaptic vesicles with metabolites and ions across the many layers of myelin. the presynaptic membrane. Asa result, packets Glial Gap Junction Genetic Diseases (quanta) of transmitter molecules are released into the synaptic cleft. Charcot- demyelinating disorder caused by single Step 5: The transmitter molecules diffuse across the Marie-Tooth mutations in a connexin gene (connexin 32) synaptic cleft and bind to specific receptors on the disease, expressed in the Schwann cell that blocks gap- membrane of the postsynaptic cell. X-linked form junction channel function Step 6: The binding of transmitter activates the Congenital Inherited mutations that prevent the function receptor, which in turn activates the postsynaptic cell. deafness of a connexin expressed in the cochlea Step 7: The process is terminated by (1) enzymatic (connexin 26) forms gap-junction channels destruction of the transmitter (e.g., hydrolysis of ACh by that are important for fluid secretion in the acetylcholinesterase), (2) uptake of transmitter into the inner ear presynaptic nerve terminal or into other cells by Na+- dependent transport systems, or (3) diffusion of the transmitter molecules away from the synapse.  NEUROSCIENCE 15" SEM 2021 poppy&lucy A IONOTROPIC RECEPTOR B METABOTROPIC RECEPTOR Axon Axon Electrical o Pe Electrical stimulus ) ( c cours stimulus y Na® / ge eo » G Ae fe Acetylcholinesterase P —. * Acetylcholine Same transmitter substance can be released differently Acetyicholine /. \\ f. \ Na* eS As cetylcholinesterase Ichol breaks breaks { /./ Atrial muscle cana from different cells. ie down acetylcholine. J j _ | Conventional transmitter, modulator, neurohormone wd a ot at musce smears G A { 7% em——— a The action of a transmitter depends on the properties of the Nicotinic ACh receptor Seana Muscarinic ACh receptor postsynaptic receptors that recognize and bind the channel activation activation transmitter. Membrane depolarization | A of a-GTP +,Pr Y from the heterotrimeric G cua | Ach canexcite some postsynaptic cells and inhibit others, and at still other cells it can produce both excitation and Action potential Activation of inward excitation rectitier K* channel by By inhibition. V Vv iaecke | Membrane Therefore, it is the receptor that determines theaction of hyperpolarization ACh, including whether a cholinergic synapse is excitatory contraction xb Decrease in heart rate or inhibitory. Two biochemical features common to all receptors for chemical transmitters: They are membrane-spanning proteins. The region exposed Same transmitter substance can be released differently from to the external environment of the cell recognizes and different cells. Conventional transmitter, modulator, binds the transmitter from the presynaptic cell. neurohormone They carry out an effector function within the target cell. The action of a transmitter depends on the properties of the The receptors typically influence the opening or closing of postsynaptic receptors that recognize and bind the transmitter. ion channels. Ach canexcite some postsynaptic cells and inhibit others, and at still other cells it can produce both excitation and inhibition. Therefore, it is the receptor that determines theaction of ACh, IONOTROPIC RECEPTOR (NMJ SKELETAL MUSCLE) including whether a cholinergic synapse is excitatory or inhibitory. e Ach-activated ion channel/Nicotinic AchR e Activation of ionotropic receptor > rapid Two biochemical features common to all receptors for chemical opening of ion channels transmitters: (Na,K)>depolarization/hyperpolarization of postsynaptic membrane activates muscle fiber They are membrane-spanning proteins. The region exposed to ¢ Mediate fast ionic synaptic 1cresponse | the external environment of the cell recognizes and binds the RECEF (milliseconds) transmitter from the presynaptic cell. They carry out an effector function within the target cell. The receptors typically influence the opening or closing of ion channels. Nicotinic AGH receptor channel activation Membrane depolarization p Action potential eS fon  NEUROSCIENCE 15" SEM 2021 poppy&lucy METABOTROPIC RECEPTOR (ATRIAL PS SYNAPSE 2 MAIN CLASSES OF CHEMICAL SUBSTANCES FOR HEART) SIGNALING ¢ Gprotein-linked achr/muscarinic achr SMALL-MOLECULE TRANSMITTERS e Activation of metabotropic G protein-linked e Packaged in small electron-lucent vesicles (40 receptor > production of a and B ysubunits nm in diameter) >activation of K channel>membrane e Release their contents through exocytosis at hyperpolarization inhibition of cardiac excitation active zones closely associated with specific e Mediate slow, biochemically mediated synaptic Ca2+ channels peptides responses (seconds-minutes) NEUROACTIVE PEPTIDES SB METABOTROPIC RECEPTOR = __- — Axon e Short polymers of amino acids see sport of J) Electrical _ stimutus e Packaged in large dense-core vesicles ( (approximately 70-250 nm in diameter) Ze e Release their contents by exocytosis, similar to holinesterase those seen in secretory glands and mast cells. rn sre SS —— = ——Acetyicholine VESICLES sterase breaks hotline. = elo Both types of vesicles are found in most neurons but in different proportions. — Muscarinic ACh receptor —— aE SMALL SYNAPTIC VESICLES: Release of «-GTP + Br e Characteristic of neurons that use ACh, | evens the heterotrimeric G protein | ae glutamate -aminobutyric acid (GABA), and Activation of inward glycine as transmitters ab rectifier K* channel! by By LARGE DENSE-CORE VESICLES Membrane hyperpotarization | a5 e Typical of neurons that use catecholamines and “Decrease heart rate in serotonin as transmitters. A CHEMICAL MESSENGER MUST MEET FOUR CRITERIA Table 13=1 Small-Molecule Transmitter Substances and Their Precursors TO BE CONSIDERED A NEUROTRANSMITTER Transmitter Precursor PROPERTIES OF A NEUROTRANSMITTER Acetylcholine Choline 1. It is synthesized in the presynaptic neuron. Biogenic amines 2. It is present in the presynaptic terminal and is Dopamine Tyrosine Norepinephrine Tyrosine released in amounts sufficient to exert a Epinephrine Tyrosine defined action on the postsynaptic neuron or Serotonin Tryptophan Histamine Histidine effector organ. Melatonin Serotonin 3. When administered exogenously in reasonable Aumine acids concentrations it mimics the action of the Aspartate Ona loaceta te yAminobutyric acid Glutamine endogenous transmitter (for example, it Glutamate Glutamine activates the same ion channels or second- Glycine Serine messenger pathway in the postsynaptic cell). ATP ADP 4. A specific mechanism usually exists for Adenosine ATP Arachidonic acid Phospholipids removing the substance from the synaptic cleft. Carbon monoxide Henne Nitric oxide Arginine NEUROSCIENCE 15" SEM 2021 poppy&lucy ACETYLCHOLINE e Only low-molecular-weight amine transmitter SYNTHESIS: substance that is not an amino acid or derived e Choline is taken up into nerve terminals by directly from one. special choline transport system mediated by a MAJOR LOCATIONS: carrier that co-transports sodium. e released at all vertebrate neuromuscular e Choline transport appears to be the rate junctions by spinal motor neurons limiting step. e autonomic nervous system: transmitter for all e = Inhibited by hemicholinium. preganglionic neurons and for parasympathetic e Choline acetylated by enzyme choline acetyl postganglionic neurons transferase to form Ach. e Form synapses throughout the brain; those in the nucleus basalis have particularly widespread STORAGE AND RELEASE: projections to the cerebral cortex. e Achis packaged into vesicles by an active e together with a noradrenergic component is a transport process coupled with the efflux of principle neurotransmitter of the reticular protons. activating system, which modulates arousal, e When an action potential propagated voltage sleep, wakefulness, and other critical aspects of sensitive calcium channels in the presynaptic human consciousness membrane opens causes an intracellular increase of calcium. NEUROTRANSMISSION AT CHOLINERGIC NEURONS e Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and e Synthesis of acetylcholine. Storage of release of their contents into the synaptic cleft. acetylcholine in vesicles. e Release can be blocked by botulinum toxin. e Release of acetylcholine. Binding to receptor. e Degradation of acetylcholine. DEGRADATION: e Recycling of choline. e Degraded by acetylcholinestrase and forms choline and acetate in the synaptic cleft. cHEHS CH cy, Acelvicholne Hh acetcaci een Me C x \ RATE +N-CH,CHzO-C-CH, > + ‘ ChAT { Wat LIMITING STEP traction 9°: CH, CH 3 ACh SNat - 4N Hs Choline ses ADP—~/ Nat, kt I Cholinergic ACh \ i. ATP \ “ATPase \ j CH,CH,OH Acetylicholinesterase varicosity Cot we K+ Cet ——» @ N e Bind to the enzyme active site. VAMPS E } Catt cr f 4 \ | / Chol e hydrolysed to acetylated enzyme and choline Co-T , Choline ACh | } adnaan SNAPS ae s / ‘ch _——__— Etfector cell v rw membrane BLACK WIDOW SPIDER 0 | je ACHE 4 ! \ nACHR NEUROSCIENCE 15" SEM 2021 poppy&lucy tubocurarine atropine TWO TYPES OF ACETYLCHOLINESTERASE hexamethonium hyoscine antagonis antagonist ENZYMES: nicotine acetylcholine muscarine agonist o o eo o a 1. True choline esterase Specific,essential for life Substrate Ach, methacholine Present in cholinergic nerve To regenerate take 120 days Slow turnover 16 nm nicotinic muscarinic receptor receptor 2. Pseudo choline estrase membrane depolarization G-protein regulated effectors (or Ca2+ entry) nonspecific ,jhydrolysed ester “jonotropic” “metabotropic” -brain, exogenous Ach, succinyl choline { Nmuscutar M1 -autonomic ganglia -glands -neuromuscular junction plasma, liver, intestine,CNS, RBCs, skin Nneuron M2 -heart -brain synthesized in liver -brain == -smooth muscle (airway, gut, -peripheral nervous system M3 bladder, eye) rapid -chromaffin cells (adrenal medulla) -glands (salivary, gastric, sweat, airway submucosal) -endothelium -brain -brain M4 TYPES OF RECEPTORS: MS -brain (substantia nigra -salivary gland 1. MUSCARINIC RECEPTOR -smooth muscle eye are G protein coupled receptor causing activation of phospholipase c IONOTROPIC RECEPTOR (NMJ SKELETAL MUSCLE) Inhibition of adenylate cyclase e Ach-activated ion channel/Nicotinic AchR Activation of potassium channels e Activation of ionotropic receptor > rapid Inhibition of calcium channels opening of ion channels 5 types (Na,K)>depolarization/hyperpolarization of Blocked by atropine postsynaptic membrane activates muscle fiber e Mediate fast ionic synaptic response 2. NICOTINIC RECEPTOR (milliseconds) e Stimulated by nicotine, on the basis of their ability to be bound by natural METABOTROPIC RECEPTOR occurring alkaloid nicotine ¢ Gprotein-linked achr/muscarinic achr e Has ligand gated ion channel---- e Activation of metabotropic G protein-linked depolarization Receptor > production of a and B ysubunits >activation of K channel>membrane TWO types: hyperpolarization inhibition of cardiac excitation e Nm (neuromuscular junction), blocked e Mediate slow, biochemically mediated synaptic by d-Tubo-curarine. responses (seconds-minutes) e Nn (postganglionic cell body), blocked by hexamethonium. NEUROSCIENCE 15" SEM 2021 poppy&lucy CATECHOLAMINE TRANSMITTERS e CNS: norepinephrine is used as a transmitter by neurons with cell bodies in the locus ceruleus, a PHENYLETHANOLAMINE-NMETHYLTRANSFERASE nucleus of the brain stem with many complex e methylates norepinephrine to form modulatory functions epinephrine (adrenaline) in the adrenal medulla Adrenergic neurons are relatively few in e Notall cells that release catecholamines express number, they project diffusely throughout the all biosynthetic enzymes cells that release cortex, cerebellum, and spinal cord. epinephrine express all ensymes PNS: norepinephrine is the transmitter of the e neurons that release norepinephrine do not postganglionic neurons in the sympathetic express the methyltransferase neurons that nervous system release dopamine do not express the transferase or dopamine B- hydroxylase e OH TYROSINE HYDROXYLASE MH a tg —CHa-BH—CHa Poa CH,—dH—coo* e converts tyrosine to I-dihydroxyphenylalanine AT Tyrosine o4 6 Epinephrine (I-DOPA) tetrahydrobiopterin tyrosine +O, e rate-limiting for the synthesis of both hydroxylase S-adenosyihomocysteine dihydrobiopterin phenylethanolamine ALmethylitran sferase dopamine and norepinephrine +H S-adenosylmethionine OH NH3 er H2—CH2-NH2 DOPAMINE HYDROXYLASE (Oct eee wo-hy AS HO OH e Third enzyme Norepinephrine HO ¢ converts dopamine to norepinephrine DOPA decarboxylase Qo, dopamine p- hydroxylase @ membrane-associated e Bound tightly to the inner surface of aminergic co, (ypc one te noe vesicles as a peripheral protein. GH Dopamine — ™. Javed Abbas m.0.° e Norepinephrine is the only transmitter synthesized within vesicles. DOPAMINE RECPETORS e There are five subtypes of dopamine receptors Aro c > ack D1-D5 S lyrosme WO \ rosie \ hywronylase e D1 and D5 increase the intracellular levels of ’ Dihydroxyphenyialanine cAMP by activating adenylate cyclase. Adrenergic {t-DOPA) e D2, D3, D4 decrease the intracellular levels of nouron \ A | \ Lamina seis cAMP by inhibiting adenylate cyclase. Acton potential \daterbcyfese Dopamine e The effect the dopamine on a neuron depends | vmar NE transporter DOPAMINE RECEPTORS: | Ne Biochemical response: Adenyl cyclase | a H' Beoanee by / _ (ne Selective Antagonists: ridone &, Dopamine (GR monapride [+ nyuronylase % Raclopride Sulpiride _ Ne 4 \ Selective Agonists: NE \ PHNO, Quinpirole \ N-0437 (hy (autorecepior) ) Mdronerge receptor DOPGAL | ] Nucleus: : J accumbens = Olfatory tubercule is Hej Synaptic Dopamine cleft D.-like receptor a h Postsynaptic adrenergic receplors Postsynaptic cell  NEUROSCIENCE 15" SEM 2021 poppy&lucy Adrenergic Receptors NORADRENALINE Alpha Beta e acts mainly on a receptors in hemodynamic +++ Norepinephrine + Epinephrine +++ Epinephrine + Norepinephrine disorders that are due to vasodilation (septic Smooth muscle contraction Smooth muscle relaxation shock) alpha = NO E = NOrEpinephrine bEta = has an E = Epinephrine e also cardiogenic shock Alpha = think of alpha in animal kingdom = dominant/strong = smooth muscle contraction Beta = think of beta fish = chill and relaxed = smooth muscle relaxation ADRENALINE e acts mainly on a and B receptors in anaphylactic Adrenergic Neurotransmission and shock {action on a receptors reduces oedemas Drugs affecting it and action on B2 recetors causes Synthesis and Metabolism of Catechol amines bronchodilation) Dopamine hyronians |] e cardiac arrest (effect on B1 receptors in the [ Tyrosine }——+| L-Dora |——+! Dopamine |——+ | Nor-Epinephrine rey Epinephrine | mao]. & heart) [mao ~ ' comMT ] comT | OO Nor-Metanephrine Alpha Receptors DOPAC Metanephrine 1. Vasoconstriction of [com | | Vanillylmandelic acid (VMA) a. Coronary arteries | Homovanillic Acid | b. Veins 2. |motility of GIT smooth muscle cells al a2 (postsynaptic) (presynaptic) Gq protein coupled Gi protein coupled DISEASE AND DISORDERS Activates Phospholipase C Inhitbits Adenyl Cyclase e Parkinson’s- stiffness of the body, slow PIP2 >IP3+ DAG ATP >X>cAMP 1. Vasoconstriction of 1. Glucose metabolism movements, and trembling of the limbs. It is blood vessels of a. Inhibits insulin release caused by massive loss of dopamine cells. a. Skin b. Stimulates glucagon b. GIT release e L-Dopa is used to treat this disease. c. Kidney 2. Contraction of anal e Dopamine drugs help treat ADHD by increasing d. Brain spinchter 2. Contraction of smooth 3. Inhibits release of the levels of dopamine in the brain. muscles of Norepinephrine e Pain and nausea can be increased with a. Ureter b. Vas deferens decreased dopamine levels in the brain. c. Urethral spinchter d. Uterus e. Ciliary body PSYCHOSIS (my diarisis) 3. Glucose metabolism e High levels of dopamine have been observed in a. Gluconeogenesis patients with schizophrenia. b. Glucolysis e Primary pathways affected by dopamine include - Beta Receptors an influx of levels in the mesolimbic pathway and a decrease in levels in the mesocortical pathway. Bl B2 (postsynaptic) (postsynaptic) SEROTONIN Gs protein coupled Activates Adenyl Cyclase ¢ serotonergic neurons are found in and around ATP > cAMP the midline raphe nuclei of the brain stem 1. The heart 1. Smooth muscle relaxation a. fheart rate (+ of e involved in regulating attention and other chronotropic) a. Bronchus complex cognitive functions b. timpulse conduction b. Bronchioles (+dromotropic) c. Detrusor muscle e Projections of these cells (like those of c. Tcontraction (+ d. Uterine muscle noradrenergic cells in the locus ceruleus) are inotropic) 2. Contraction of urethral d. fejection fraction spinchter widely distributed throughout the brain and 2. frenin release by 3. frenin release by spinal cord. Juxtaglomerular cells Juxtaglomerular cells 3. thunger 4. Glucose metabolism a. Tghrelin release by a. Inhibits insulin release stomach b. Stimulate i. Gluconeogenesis ii, Glucolysis 5. Lipolysis 6. Thickened salivary secretion  NEUROSCIENCE 15° SEM 2021 poppy&lucy CLINICAL IMPLICATIONS PNS Serotonin and the catecholamines e Pain norepinephrine and dopamine are implicated e itch in depression, a major mood disorder. Antidepressant medications inhibit the uptake CLINICAL USE of serotonin, norepinephrine, and dopamine, thereby increasing the magnitude and e adiagnostic agent duration of the action of these transmitters, e to assess nonspecific bronchial hyperreactivity which in turn leads to altered cell signaling and in asthmatics adaptations ¢ asa positive control injection during allergy skin testing Tryptophan (Trp) 0,+BH, TOXICITY AND CONTRAINDICATIONS H,0+BH, 2] Tryptophan hydroxylase (TPH) 1 and 2 \e e Flushing, hypotension,tachycardia, headache 5-Hydroxytryptophan (5-HTP) wheals, brochoconstriction, gastrointestinal A Aromatic Amino Acid Decarboxylase (AADC) co, upset a ee 5-Hydroxytryptamine (Serotonin, 5-HT) HiIN N COOH Monoamine oxidase (MAO) A and B Serotonin N-acetyltransferase (SNAT) A -Histidine Aldehyde dehydrogenase (ALDH) 7 \gHydroxyindole O-methyltransferase (HIOMT) 9 “Histidine decarboxylase HN N 5-Hydroxyindole acetic acid (5-HIAA) Melatonin oe Histamine Diamine Histamine-N-methyl oxidase transferase Limiting reaction: tryptophan hydroxylase CH,— CH—NH2 HN N HsC —N N *study table 11-1 TP snidazons “SH 1-ethyihistamine | acetaldehyde CH2— COOH | A-Methythistamine oxidase CH2— COOH HN N = = “SF midazote H3sC —N N HISTAMINE | acetic acid “SS N-Mathylimidazole acetic acid long been recognized as an autacoid, active Conjugates with ribose-phosphate when released from mast cells in the inflammatory reaction and in the control of Receplor Distribution Postreceptor Partially Selective Agonists Partially Selective Mechanism Antagonists vasculature, smooth muscle, and exocrine one Smooth muscle, endothelium, brain Sy IPs, BAG Histaprodifen Mepyramine, glands (eg, secretion of highly acidic gastric triprofidine, cetirizine juice) He Gastric mucosa, cardiac muscle, mast Sy AMP Amthannine Cimetidine,' raniti calls, brain dine," tiotidine ‘ a transmitter in both invertebrates and Presynaptic: brain, myenteric plescus, & cAMP R—Methylhistamine, imetit, Thioperamide, other neurons immepip iodophenprapit, vertebrates clobenpropit,' tiprolisant' concentrated in the hypothalamus, one of the Eosinophils, neutrophils, CD4 T calls G cAMP Clobenpropit, imetit, Thioperamide centers for regulating the secretion of clozapine hormones CNS regulation of drinking body temperature secretion of antidiuretic hormone control of blood pressure perception of pain wakefulness  NEUROSCIENCE 15" SEM 2021 poppy&lucy AMINO ACID NEUROTRANSMITTERS RECEPTOR MODULATORY SITE SITES GLUTAMATE e most frequently used at excitatory synapses NMDA antagonists \ throughout the central nervous system Glutamate Glycine e Produced from a ketoglutarate, an intermediate Polyamines in the tricarboxylic acid cycle of intermediary ‘ Polyamine metabolism. ‘ antagonists e After it is released, glutamate is taken up from the synaptic cleft by specifc transporters in the membrane of both neurons and glia. NMDA receptor e Glutamate taken up by astrocytes is converted to glutamine by the enzyme glutamine synthase TMoa tsar glutamine then diffuses back into neurons that Kynureneic Antagonist at glycine binding site Antiexcitotoxic, acid anticonvulsant use glutamate as a transmitter, where it is Ketamine Non competitive antagonist at NMDA Anesthetic, pain hydrolyzed back to glutamate. IM: 2-4 mg/kg, IV: 0.2-0.75 mg/kg management. ADR: High BP, cerebro- e Phosphate-activated glutaminase (PAG), which vascular accident is present at high concentrations in these Phencyclidine | NMDAreceptor antagonist Recreational drug neurons, is responsible for salvaging the Dizocilpine NMDA receptor antagonist Anticonvulsant, dissociative anesthetic, molecule for reuse as a transmitter stroke, Huntington's disease etc. Neuron Astrocyte Glucose Glucose Remacemide _Low affinity NMDA receptor Stroke, epilepsy Presynapse antagonist ADR: dizziness, nausea OY np une Pyruvate co, aan 17.5% eke Extracellular Memantine Non competitive NMDA receptor Alzheimer's disease, € space ae laucoma antagonist -interacts with the Mg2+ ~ 8 10-30 mg/day Glutamine ~—_ Glutamine | binding site of the channel to prevent ADR: confusion, Glutamate ——————— Jutamate excessive activation while sparing hypertonia, cystitis Blood normal function (approx. 3-7%) Perivascular space (approx. 5%) Riluzole Presynaptically inhibits glutamate Amyotrophic lateral sclerosis Lactate release PO: 50mg BD Post synaptically blocks postsynaptic ADR: dizziness, weight loss Aerobic glycolysis (AG)? NMDA- and kainate-type glutamate A lonotropic glutamate receptor receptors and inhibits voltage-dependent Na+ AMPA or Kainate NMDA channels, Na Nag —* B= Mg?" Amantadine Blocks NMDA glutamate receptors Parkinson's disease (neurotoxicity, dyskinesia) “8 PO: 100-200mg/day ADR: hallucination, ankle edema. Eliprodil NMDA antagonist (polyamine site) Failed in clinical trial II! Dextrometharphan NMDA-receptor antagonist and acts Antitussive agent centrally to elevate the threshold for PO:10mg TDs i coughing. Methadone NMDA receptor antagonist 2.5-10mg q8-12:n hourly Ke ADR: sedation, fatigue Glutamate Acamprosate Weak antagonist of NMDA receptors, —_Anticraving drug activator of GABAa receptors ADR: GIT upset, skin eruption lon channel-associated G protein-coupled Herbal drugs acting on NMDA Ginseng “% Ginkgo biloba Fast Slow Slow excitatory excitatory inhibitory Curcuma longa  NEUROSCIENCE 15" SEM 2021 poppy&lucy GLYCINE NEUROTRANSMISSION GABA e major transmitter used by inhibitory ¢ present at high concentrations throughout the interneurons of the spinal cord central nervous system e Anallosteric modulator of the N- methyl-d- e Used as a transmitter by an important class of aspartate (NMDA) subtype of glutamate inhibitory interneurons in the spinal cord. receptors synthesized from serine. e Brain GABA is the major transmitter of various e specific biosynthesis in neurons is not well inhibitory neurons and interneurons, such as understood, but its biosynthetic pathway in the medium spiny neurons of the striatum, other tissues is well known striatal interneurons, basket cells of both the cerebellum and the hippocampus, the Purkinje SUMMARY OF GLYCINE SYNTHESIS, RELEASE, cells of the cerebe