Lecture_13-Catecholamines

Origins pons and medulla a6a4 locus coeruleus caudal

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Origins: Pons and medulla A6/A4: Locus coeruleus + caudal extension A5/A7: Lateral tegmental area A2: dorsal medullary group DA - Dopamine A10: substantia nigra pars compacta (SNc) - Nigrostriatal pathway A9: ventral tegmental area (VTA) Arcuate nucleus (hypothalamus) Mesolimbic dopamine pathway Relatively discrete projections of the major catecholamine pathways in the brain
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What are Catecholamines ? Molecules with a catechol nucleus and an ethylamine group attached in position 1 All are synthesized from a common pathway originating from tyrosine (dietary essential amino acid) Tyrosine is actively transported across BBB
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TH - requires tetrhydrobiopterin (hydrogen donor) - rate-limiting enzyme that is inhibited by AMPT AADC - Localized to dopamine neurons (formerly dopamine decarboxylase) - Fast-acting enzyme - Requires pyridoxal phosphate (from vitamin B6) as a cofactor DBH - Localized to NE neurons (of brain and sympathetic nervous system) - Requires vitamin C as a cofactor PNMT - Localized to adrenergic neurons and adrenal medulla * Tyrosine is typically saturated
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Catecholamine Pathway Simplified Tyrosine Dopa Dopamine Norepinephrine Epinephrine TH AADC DBH PNMT
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Short-Term Regulation of TH End-product enzyme inhibition (ie. DOPA inhibits TH) Regulated at the transcriptional, translational and post- translation levels Rapid, short-term regulation – Phosphorylation and dephosphorylation at 4 key serine residues – Phosphorylation induces a conformational change in enzyme that increases affinity for co-factor and reduces affinity of catecholamine (reduces end-product feedback) increase in catalytic activity increase in DA, NE and Epi
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Long-Term Regulation of TH Longer term regulation occurs through transcriptional regulation of the TH gene – TH promoter contains several regulatory elements including: CRE, GRE, AP-1 – CRE appears to be critical for chronic up-regulation of gene transcription
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Catecholamine Storage Vesicular storage H + ATP-ase & VMAT (vesicular monoamine transporter) mediate vesicular packaging VMAT blocked by reserpine ; causes temporary increase in cytosolic neurotransmitter levels followed by a decrease in NT packaged in vesicles --> no vesicular DA released upon AP
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NE Storage -in NE neurons , vesicles also contain DBH to convert DA to NE -in blocking DA uptake into vesicles, reserpine also reduces NE levels - Amphetamines enter through VMAT, disrupt pH of vesicle à drives DA/NE out into cytosol
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Origins Pons and medulla A6A4 Locus coeruleus caudal...

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