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BASIC NEUROTRANSMITTER

BASIC NEUROTRANSMITTER. Catecholamines (dopamine [DA], norepinephrine [NE], epinephrine [EPI]). Basic Neurochemistry , Chap. 12 The Biochemical Basis of Neuropharmacology , Chap. 8 & 9. Biosynthesis of Catecholamines. Important fetures of catecholamine biosynthesis, uptake and signaling.

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BASIC NEUROTRANSMITTER

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  1. BASIC NEUROTRANSMITTER

  2. Catecholamines(dopamine [DA], norepinephrine [NE], epinephrine [EPI]) Basic Neurochemistry, Chap. 12 The Biochemical Basis of Neuropharmacology, Chap. 8 & 9

  3. Biosynthesis of Catecholamines

  4. Important fetures of catecholamine biosynthesis, uptake and signaling • Biosynthesis • Release • Uptake (transporter) • Receptor-mediated signaling • Catabolism

  5. Tyrosine hydrogenase: rate-limiting enzyme • TH is a homotetramer, each subunit has m.w. of 60,000 • Catalyzes –OH group to meta position of tyrosine • Km = M range; saturation under normal condition • Cofactor: biopterin; competitive inhibitor: -methyl-p-tyrosine • Sequence homology: phenylalanine hydroxylase and tryptophan hydroxylase • Phosphorylation at N-terminal sites:

  6. Phosphorylation sites of Tyrosine Hydroxylase

  7. Modulation of catecholamine synthesis • Neuronal activity increase would enhance the amount of TH and DBH at both mRNA and protein levels • TH is modulated by end-product inhibition (catecholamine competes with pterin cofactor) • Depolarization would activate TH activity • Activation of TH involves reversible phosphorylation (PKA, PKC, CaMKs and cdk-like kinase)

  8. Dopa decarboxylase • Cofactor: pyridoxine (Vitamin B6); • Also decarboxylate 5-HTP and other aromatic a.a.:aromatic amino acid decarboxylase (AAAD) • Inhibitor: -methyldopa Dopamine -hydroxylase • Cofactor: ascorbate; substrate: dopamine • Inhibitor: diethyldithiocarbamate (copper chelator) • DBH is a tetrameric glycoprotein (77kDa and 73kDa) • Store in the synaptic vesicle and releasable Phenylethanolamine N-methyltransferase (PNMT) Substrate: S-adenosylmethionine; regulated by corticosteroids

  9. Catecholamines packed into the synaptic vesicles VMAT2: Non-selective and has high affinity to reserpine

  10. Metabolism of dopamine • Major acidic metabolites: • 3,4-dihydroxy phenylacetic acid (DOPAC) • Homovallinic acid (HVA)

  11. Inactivation of Norepinephrine

  12. Monoamine oxidase (MAO) • Cofactor: flavin; located on the outer membrane of mitochondria • Convert amine into aldehyde (followed by aldehydedehydrogenase to acids or aldehyde reductase to glycol) • MAO-A: NE and 5-HT (inhibitor: clorgyline); MAO-B: phenylethylamines (DA) (inhibitor: deprenyl) • Patient treated for depression or hypertension with MAO inhibitors: severe hypertension after food taken with high amounts of tyramine (cheese effect) Catechol-O-methyltransferase (COMT) • Enzyme can metabolize both intra- or extracellularly • Requires Mg2+ and substrate of S-adenosylmethionine

  13. Uptake of catecholamines: transporter

  14. Uptake transporters • Released catecholamines will be up-take back into presynaptic terminals (DAT, NET) • Transporter is a Na+ and Cl+-dependent process (ouabain [Na,K-ATPase inhibitor] and veratridine [Na channel open] block uptake process)

  15. 3. Transporter is saturable, obeys Michaelis-Menten kinetics 4. 12 transmemebrane domain: intracellular phosphorylation and extracellular glycosylation 5. Uptake is energy dependent; can be blocked by tricyclic antidepressents, cocaine, amphetamine and MPTP

  16. Regulation of DAT by various protein kinases

  17. Localization of catecholamine neurons • Immunocytochemistry (ICH): antibody against synthesis enzyme, uptake transporter and receptor • In situ hybridization (ISH): cDNA or cRNA probe synthesis enzyme, transporter and receptor • Receptor autoradiography: radiolabelled ligand ([3H] or [125I]) against receptor

  18. Noradrenergic projection (dorsal and ventral bundle) Cortex and hippocampus Dorsal bundle Spinal cord cerebellum (Locus ceruleus) Hypothalamus and Brainstem Ventral bundle

  19. Dopamine projections (nigrostriatal, mesocortical, tuberohypophysial) Nigrostriatal projection Substantia nigra to caudate/putamen n. Tuberohypophysial projection Mesocotical projection Ventral tegmental area to nucleus accumbens and frontal cortex Hypothalamus to median eminence

  20. Catecholamine receptors • Postsynaptic receptors locate on dendrites or cell body, axons or nerve terminals • Presynaptic autoreceptors locate on the same neuron: • a. terminal autoreceptor: control release • b. somatodendritic autoreceptor: synthesis control • c. major autoreceptor type: 2-adrenergic receptor in PNS/CNS; D2-dopamine receptor • d. exception: -adrenergic receptor facilitates NE release

  21. Autoreceptor: inhibit transmitter release

  22. Classification of Dopamine receptors

  23. Feature of Dopamine receptors • Two subtypes of dopamine receptor: D-1 (short i3, long C-terminal) and D-2 like (long i3, short C-terminal) receptors • D2 receptors contain splicing isoform: D2L and D2S (87 bp) • D3 receptor has high affinity to atypical neuroleptics; D4 receptor bind tightly with clozapine • Chronic antagonist treatment up-regulate D2 receptors; agonist treatment might down-regulate the D2 receptor • Pharmacological application: anti-Parkinson (D2 agonist), anti-psychotic (D2 antagonist), addictive drugs (DA transporter)

  24. 2-D structure of dopamine D2 receptor

  25. Classification of Adrenergic receptors

  26. Features of Adrenergic receptors • Both NE and epinephrine bind to  and  receptors • 1 locates mainly in the heart and cortex; 2 predominate in the lung and cerebellum; 3 in the adipose tissue (significance in obesity) • -receptor stimulates AC; in turn, inactivates receptor via ARK and -arrestin • 1 is a post-synaptic receptor (three subtypes: 1A, 1B and 1D); while 2 is both post- and pre-synaptic receptor (three subtypes: 2A, 2B and 2C) • Representative ligands: propranolol ( antagonist),yohimbine ( agonist)

  27. propanolol yohimbine

  28. GPCR-mediated signal and internalization

  29. Dynamics of catecholamine receptors (up-regulation and down-regulation) agonist antagonist catecholamine receptor

  30. SEROTONIN

  31. Serotonin Serotonin is used throughout the body in multiple physiological roles. 90% of all serotonin in human body in the GI tract. 8% in blood platelets. 2% in CNS. Neurons in brain make their own; none from body crosses Blood Brain Barrier (BBB).

  32. Synthesis: Tryptophan 5 hydroxytryptophan5 hydroxytryptophan 5hydroxytryptamine(5HT)1.Tryptophan hydroxylase (rate limiting step)High serotonin levels within neuron do not inhibit enzyme synthesis-serotonin just builds up.Rate of enzyme activity can be modulated by second messengers involving cAMP. Also, can be modulated by Oxygen levels in blood; more oxygen, more synthesis of serotonin.

  33. 2.5-hydroxytryptophan( 5HTP) decarboxylase: • Production of enzyme and use to make serotonin very rapid. • Can't manipulate serotonin by manipulating this enzyme. • N.B. Release of serotonin is Ca++ dependant, Ca++ must come into trigger release.

  34. Deactivation and Breakdown • Action terminated by active re-uptake process into neurons and ganglia. • Then broken down by MAO. • MAO breaks down 5HT into several things. • 5-hydrozindoleacetic acid (5HIAA) is a metabolite that is often used to index activity in system; measured in CSF( cerebrospinal fluid).

  35. Receptors • 7 major types;3 of relevance to current set of medications: • 5HT1 “slow inhibition”: through G proteins, reduce adenylyl cyclase activity; exists as postsynaptic and presynaptic receptors. • 5HT2 “slow excitation": through G proteins, increase K+ & Ca++ influx.CNS has mostly 5HT1A (found in prefrontal cortex). • 5HT3 “Fast excitation”: ion-coupled to Na+;some modulation also of Ca++ channels in the area of postrema,trigger vomiting.

  36. Serotonin Pathways in Brain

  37. Serotonin Pathways in Brain • Serotonin is released as neurotransmitter but also released non-synoptically through some axon terminals. • Neurotransmitter pathways can be consolidated into 3 major paths. • All paths emerge from same set of neurons in the Raphe region of the brainstem, a group of nuclei along midline of midbrain,pons and medulla.

  38. 1.Caudal pathway(from Raphe nuclei to medulla and spinal cord) • Uses mainly 5HT1 receptors " slow excitation”. • Causes contraction or uterine muscles cramps. • Causes some contraction of blood vessel walls" blood pressure”. • Causes mild motor neuron excitation. • Stimulates release of endorphins that then inhibit pain messages. • 5HT3 receptors in area postrema trigger vomiting.

  39. 2.Middle pathway(from Raphe neurons to cerebral cortex and basal ganglia) • Goes to cortex along with NE axons. • Goes to basal ganglia along with DA & ACh neurons. • 5HT2 “slow excitation” receptors. • Serotonin induces positive mood and affect cortex. • “This is the system where SSRIs work by inhibiting the transporter protein necessary for serotonin reuptake”.

  40. 3.Rostral pathway:(from Raphe nuclei to 5 areas) • Uses 5HT1 “slow inhibition” &5HT2 “slow excitation” • A. Raphe nuclei within):within Raphe,there are autoreceptors(5HT1-self inhibit) • B. Raphe to sensory cortex:Sensory cortex-particularly visual perception-5HT2 relevant to hallucinogens(LSD,psilocybin mushrooms) • C. Raphe to limbic system:Limbic system “Pleasure & anxiety” slow inhibition at 5HT1 receptors. • D. Raphe to hypothalamus and thalamus:Uses 5HT1 receptors in thermoregulation.Ecstasy causes hyperthermia through here. • E. Raphe to suprachiasmatic nucleus:Uses 5 HT1.Important in sleep/wakefulness.Serotonin induces sleep-inject into brain-sleep occurs.Inhibit serotonin (by PCPA,inhibits Tryptophan hydroxylase and production of serotonin); no sleep and there is an increase in activity.But other neurotransmitter are also important in sleep.

  41. CNS Relevant diseases • Depression • Anxiety • Possible some interactive role in Schizophrenia • Ecstasy “empathogen” • High levels of Amphetamine • LSD and psilocybin mushroom hallucinogens • Migraine headache(5HT1 agonists cause constriction of intracranial blood vessels; may block endogenous inflammatory agents)

  42. Drugs used to treat depressive disorders: • MAO inhibitors. • Tricyclic antidepressants • SSRIs “selective serotonin reuptake inhibitors” • Other serotonergic drugs

  43. Ionotropic Synapses EPSP

  44. Diseases due to lack of certain neurotransmitters • GABA • Anxiety disorders, Epilepsy • Glutamate • Amyotrophic lateral sclerosis ( Lou Gehrig’s disease ) • Glycine • Hereditary hyperekplexia

  45. Additional Information on Gamma - AminoButyric Acid (GABA) What is GABA ? GABAis one of the most abundant inhibitory neurotransmitters

  46. GABAgives birth to mortality?! Cortex V1 GABA/ Muscimol Neurons Regenerated Monkeys become Active

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