Serotonergic neurotransmission Flashcards
History
Was crystallised from blood in 1948.
In 1949, the molecular structure was identified.
Primary target of psychedelics
5-HT2A/C - Gaq-coupled, increasing levels of IP3 and DAG
Pathways (originating from where, going to where)
Project from the raphe nuclei and the caudal raphe neurones.
Raphe nuclei projects to the forebrains, thalamus, and cerebellum
The caudal raphe neurones project to the spine and at the cerebellum.
5-HT synthesis
Tryptophan -> 5-OH-tryptophan -> 5-HT
tryptophan -> 5-hydroxytryptophan catalysed by tryptophan hydroxylase, with BH4, NADPH and metal ion (Fe or Cu) as cofactors
5-hydroxytrytophan -> 5-HT catalysed by aromatic amino acid decarboxylase
Other AAs compete with tryptophan to enter the brain. Plasma cortisol decreases free plasma tryptophan - decreasing amount found in brain.
Melatonin synthesis
synthesised from 5-HT. 5-HT -> N-acetyl serotonin -> melatonin
5-HT -> N-acetyl serotonin catalysed by 5-HT N-acetyltransferase
N-acetyl serotonin -> melatonin catalysed by 5-hydroxyindole-O-methyltransferase
this occurs in the pineal gland.
light inhibits melatonin biosynthesis, N-acetyl transverse activity lower in day
Melatonin disease preventing mechanism, and effect on melatonin in diseases
Decreased melatonin in AD and ageing brains.
anti-aging and antioxidant function in brain. enhances lifespan.
Circadian dysfunction can play a part in the development of amyloid plaques, and in tau pathology.
Melatonin inhibits genes BACE1 and PSEN1, reducing AD risk
5-HT metabolism
5-HT -> 5-hydroxyacetaldehyde -> 5-HIAA
5-HT-> 5-hydroxyindole acetaldehyde catalysed by MAO-A
5-hydroxyindole acetaldehyde -> 5-HIAA catalysed by aldehyde dehydrogenase, then renally excreted.
MAO
Both isoforms found in neurones and glia.
MAO-A found in liver.
MAO-B found in platelets
MAO-A for 5-HT, NA, and adrenaline
MAO-B for DA
SERT polymorphism
the promoter region of the gene can have 14 or 16 repeats. 14 repeats associated with lower transcription of SERT - associated with anxiety
5-HT receptors
14 isoforms, 7 families
5-HT3A/B/C are LGICs - Na, Ca
Rest are GPCRs
5-HT2A/B/C Gq
5-HT1A-F and 5-HT5A/B Gi/o
5-HT4/6/7 are Gs
Gs increase cAMP
Gi/o decrease cAMP
Gq increase IP3 and DAG
Presynaptic 5-HT
5-HT1A/B are presynaptic
Pathological and physiological roles of 5-HT
5-HT2 found in hypothalamic neurones with endocrine function e.g., cortisol
Low 5-HT in migraine.
5-HT4 and hippocampal synaptic plasticity
5-HT4 agonists were found to decrease the effects of LTP and LTD in the hippocampus of rats.
