Catecholamines Flashcards
1
Q
Catecholamines
A
- Molecules w/ benzene rings containing 2 adjacent hydroxyl residues and a side chain amine
- Are synthesized from tyrosine
- Liver controls availability of tyrosine and its precursor phenylalanine
- Tyr can also be obtained from high-protein foods
2
Q
Biosynthesis of tyrosine
A
- Phe is converted to Tyr by phenylalanine hydroxylase
- Mutations in this nz can lead to accumulation of neurotoxic phenylketones (phenylketonuria, or PKU)
- Decarboxylation of phe leads to phenylethylamine, which is elevated in the crises of paranoid schizophrenics
- Tyrosine decarboxylation leads to tyramine (sympathomimetic), which has actions similar to epinephrine (is also present in cheese, beer, wine, chocolate)
3
Q
Biosynthesis of L-DOPA
A
- Tyr hydroxylase (TH) converts tyr into L-DOPA, this is the rate-limiting step in catecholamine (CA) synthesis
- TH is most important nz in CA synthesis
- TH is in all cells capable of synthesizing CAs
- TH inhibited by AA analogs (alpha-methyltyrosine), CA-derivatives, Fe chelators, and lead
- Short-term regulation of TH activity occurs thru phosphorylation (increasing activity)
- Long-term regulation of TH thru transcriptional regulation by NTs, hormones, caffeine, and nicotine
4
Q
Biosynthesis of dopamine (DA)
A
- Action of DOPA decarboxylase, aromatic acid or dihydroxyphenylalanine decarboxylase (AADC) converts L-DOPA into DA
- Vit B6 is cofactor
- Nzs are present in excess
5
Q
Biosynthesis of dopamine (DA)
A
- Action of DOPA decarboxylase, aromatic acid or dihydroxyphenylalanine decarboxylase (AADC) converts L-DOPA into DA
- Vit B6 is cofactor
- Nzs are present in excess
6
Q
Biosynthesis of norepinephrine (NE)
A
- Synthesized from dopamine beta-hydroxylase nz, requires vit C, Cu, O2
- NE plays important role in sleep, arousal, attention, vigilance, learning, and memory
7
Q
Catecholamine catabolism 1
A
- Monoamine oxidases (MAO) convert the amino group to aldehyde (two types: A and B)
- MAO is preceded by or followed by COMT, then followed by aldehyde reductase, to produce a hydroxyl group from the aldehyde, or by aldehyde dehydrogenase, to produce a carboxyl group
- 1-deprenyl is a MAO-B inhibitor and can increase the T1/2 of DA
- Smoking inhibits MAO-B activity, increasing the T1/2 of DA and could be relevant to addiction
- Nicotine also stimulates the cholinergic receptors on DA neurons causing them to fire APs and release DA
8
Q
MAO mutations
A
- Abnormal and violent behavior in a family is associated w/ a point mutation in the MAO-A gene
- Pts do not have detectable amounts of HVA (CA breakdown product) and low amounts of 5HIA (serotonin breakdown product)
- MAO-B does not compensate for loss of MAO-A
- MAO-B KO in mice lead to submissive behavior
9
Q
MAO mutations
A
- Abnormal and violent behavior in a family is associated w/ a point mutation in the MAO-A gene
- Pts do not have detectable amounts of HVA (CA breakdown product) and low amounts of 5HIA (serotonin breakdown product)
10
Q
DA and NE catabolism
A
- Principle metabolite of DA after action of MAO + COMT followed by aldehyde dehydrogenase is homovanillic acid (HVA)
- HVA is an indicator of DA activity in the CNS
- Principle metabolite of NE after the action of MAO + COMT + aldehyde dehydrogenase is 3-methyle-4-hydroxyphenol-glycol (MHPG)
- MHPG is an indicator of NE activity in the CNS
11
Q
DA and NE catabolism
A
-Principle metabolite of DA after action of MAO + COMT followed by aldehyde dehydrogenase is homovanillic acid (HVA)
12
Q
DA systems of the brain
A
- DA neurons that originate in substantia nigra project to the striatum
- Those that originate in VTA project to nucleus accumbens (NA), cerebral cortex, and hypothalamus
- DA in NA is where the DA rush occurs, associated w/ drugs, sex, and risk-taking
13
Q
DA storage and release
A
- DA release requires an influx of Ca ions and the fusion of synaptic vessels
- Membrane potentials and DA synthesis/release can be regulated by presynaptic receptors
- DAT (dopamine transporter) reuptakes DA into presynaptic cells
- DAT inhibited by cocaine
14
Q
DA receptors
A
- 5 major types and all are GPCRs
- D1 and D5: stimulate cAMP synthesis by AC
- D2-4: inhibit cAMP synthesis by AC
- Present in presynaptic cells to regulate NT release
15
Q
Other compounds affecting CA pathways
A
- Alpha-methyltyrosine: inhibits TH and prevents CA production
- Reserpine: blocks DA uptake (VMAT) and storage
- Amphetamine: stimulates release of DA and blocks its uptake
- Cocaine: inhibits DAT
- Pargyline: inhibitor of MAO
