Catecholamines (dopamine [DA], norepinephrine [NE], epinephrine [EPI]) 1. Basic Neurochemistry,...
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Transcript of Catecholamines (dopamine [DA], norepinephrine [NE], epinephrine [EPI]) 1. Basic Neurochemistry,...
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Catecholamines(dopamine [DA], norepinephrine
[NE], epinephrine [EPI])
1. Basic Neurochemistry, Chap. 12
2. The Biochemical Basis of Neuropharmacology, Chap. 8 & 9
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Biosynthesis of Catecholamines
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Important fetures of catecholamine biosynthesis, uptake and signaling
1. Biosynthesis
2. Release
3. Uptake (transporter)
4. Receptor-mediated signaling
5. Catabolism
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Tyrosine hydrogenase: rate-limiting enzyme
1. TH is a homotetramer, each subunit has m.w. of 60,000
2. Catalyzes –OH group to meta position of tyrosine
3. Km = M range; saturation under normal condition
4. Cofactor: biopterin; competitive inhibitor: -methyl-p-tyrosine
5. Sequence homology: phenylalanine hydroxylase and tryptophan hydroxylase
6. Phosphorylation at N-terminal sites:
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Phosphorylation sites of Tyrosine Hydroxylase
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Modulation of catecholamine synthesis1. Neuronal activity increase would enhance the
amount of TH and DBH at both mRNA and protein levels
2. TH is modulated by end-product inhibition (catecholamine competes with pterin cofactor)
3. Depolarization would activate TH activity
4. Activation of TH involves reversible phosphorylation (PKA, PKC, CaMKs and cdk-like kinase)
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Dopa decarboxylase1. Cofactor: pyridoxine; low Km but high Vmax
2. Also decarboxylate 5-HTP and other aromatic a.a.: aromatic amino acid decarboxylase (AAAD)
3. Inhibitor: -methyldopa
Dopamine -hydroxylase1. Cofactor: ascorbate; substrate: dopamine
2. Inhibitor: diethyldithiocarbamate (copper chelator)
3. DBH is a tetrameric glycoprotein (77kDa and 73kDa)
4. Store in the synaptic vesicle and releasable
Phenylethanolamine N-methyltransferase (PNMT)Substrate: S-adenosylmethionine; regulated by corticosteroids
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VMAT2:
Non-selective and has high affinity to reserpine
Catecholamines packed into the synaptic vesicles
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Metabolism of dopamine
Major acidic metabolites:
A. 3,4-dihydroxy phenylacetic acid (DOPAC)
B. Homovallic acid (HVA)
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Inactivation of Norepinephrine
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Monoamine oxidase (MAO)1. Cofactor: flavin; located on the outer membrane of mito
chondria
2. Convert amine into aldehyde (followed by aldehyde dehydrogenase to acids or aldehyde reductase to glycol)
3. MAO-A: NE and 5-HT (inhibitor: clorgyline); MAO-B: phenylethylamines (DA) (inhibitor: deprenyl)
4. 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) 1. Enzyme can metabolize both intra- or extracellularly
2. Requires Mg2+ and substrate of S-adenosylmethionine
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Uptake of catecholamines: transporter
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Uptake transporters1. Released catecholamines will be up-take back int
o presynaptic terminals (DAT, NET)2. Transporter is a Na+ and Cl+-dependent process (o
uabain [Na,K-ATPase inhibitor] and veratridine [Na channel open] block uptake process)
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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
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Regulation of DAT by various protein kinases
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Localization of catecholamine neurons
1. Immunocytochemistry (ICH): antibody against synthesis enzyme, uptake transporter and receptor
2. In situ hybridization (ISH): cDNA or cRNA probe synthesis enzyme, transporter and receptor
3. Receptor autoradiography: radiolabelled ligand ([3H] or [125I]) against receptor
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Noradrenergic projection(dorsal and ventral bundle)
Dorsal bundle
(Locus ceruleus)
Spinal cordcerebellum
Cortex and hippocampus
Ventral bundle
Hypothalamus and Brainstem
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Dopamine projections(nigrostriatal, mesocortical, tuberohypoph
ysial)
Nigrostriatal projection
Mesocotical projectionTuberohypophysial projection
Substantia nigra to caudate/putamen n.
Ventral tegmental area to nucleus accumbens and frontal cortexHypothalamus to median
eminence
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Catecholamine receptors
1. Postsynaptic receptors locate on dendrites or cell body, axons or nerve terminals
2. 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
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Autoreceptor: inhibit transmitter release
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Classification of Dopamine receptors
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Feature of Dopamine receptors
1. Two subtypes of dopamine receptor: D-1 (short i3, long C-terminal) and D-2 like (long i3, short C-terminal) receptors
2. D2 receptors contain splicing isoform: D2L and D2S (87 bp)
3. D3 receptor has high affinity to atypical neuroleptics; D4 receptor bind tightly with clozapine
4. Chronic antagonist treatment up-regulate D2 receptors; agonist treatment might down-regulate the D2 receptor
5. Pharmacological application: anti-Parkinson (D2 agonist), anti-psychotic (D2 antagonist), addictive drugs (DA transporter)
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2-D structure of dopamine D2 receptor
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Classification of Adrenergic receptors
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Features of Adrenergic receptors
1. Both NE and epinephrine bind to and receptors
2. 1 locates mainly in the heart and cortex; 2 predominate in the lung and cerebellum; 3 in the adipose tissue (significance in obesity)
3. -receptor stimulates AC; in turn, inactivates receptor via ARK and -arrestin
4. 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)
5. Representative ligands: propranolol ( ntgonist), yohimbine ( gonist)
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propanolol
yohimbine
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GPCR-mediated signal and internalization
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Dynamics of catecholamine receptors
(up-regulation and down-regulation)
catecholamine receptor
agonist
antagonist