5-HYDROXYTRYPTAMINE AND

ITS RECEPTORS

Presented by
A.DESSOSAA MANOJ
(BVT15015) 1
 HISTORY
• In 1935, Italian Vittorio Erspamer showed an
extract from entero-chromaffin cells - made
intestine contract and named as enteramine.
• In 1948, Maurice M Rapport , Arda Green, Irvine
Page discovered vasoconstrictor substance in
blood serum –serotonin.
• In 1952,both were shown to be 5-HT.

2
 SEROTONIN
• Serotonin is a monoamine
neurotransmitter derived from tryptophan.
• Stored in granules like catecholamine.
• Also present in plants and insects .
• Plants like tomato, banana, pineapple
• Lower animals–mollusks, arthropods,
snake and bee venom /sting

3
 Synthesis, metabolism and storage
• Dietary tryptophan
converted to 5-hydroxy tryptophan by tryptophan hydroxylase
then to 5-HT by non-specific decarboxylase
• Degradation
mainly by MAO
5-hydroxyls indole acetic acid (5-HIAA) in urine

4
5
 SEROTONIN UPTAKE
• Non specific decarboxylase produces 5-HT (also CA).
• Amine pump(SERT) actively takes up serotonin (like CA) in
serotonergic nerve endings- Na+ dependent carrier inhibited by
SSRI and TCA .
• Platelets do not synthesize 5-HT (deficiency of tryptophan
hydroxylase)-but actively takes up by SERT – during passage.
• Stored in storage vesicles by active uptake –VMAT .

6
7
 SEROTONERGIC RECEPTORS
• Gadum and Picarelli(1957) classified 5-HT receptors based on
blockade by dibenzyline and morphine into
musculotropic (D –type )
neurotropic (M – type)
• Methysergide and cyproheptamide blocked D type only.
• The present system of classifying 5-HT receptors is based on
molecular characterization and cloning of receptors of cDNAs.

8
 ..
• Four families 5-HT1,5-HT2,5-HT3,5-HT4-7 comprising of 18
receptor subtypes.
• All are GPCR except 5-HT3 which is ligand gated Na + channel.
• All are cAMP except 5-HT2(IP3-DAG)
• 5-HT1 inhibits cAMP
• 5-HT 4,6,7 increases cAMP

9
10
5-HT 1- RECEPTORS
• Five subtypes A,B,D,E,F
• All subtypes couple with Gi/Go protein and inhibit adenyl
cyclase-inhibits firing of neurons or release of 5-HT
Also,5-HT1A activates k+ channels (resulting in
hyperpolarisation) and inhibits Ca2+ channels.
• 5-HT1A-Brainstem (raphe nuclei) and hippocampus(buspirone-
partial agonist)
• 5-HT1D-Basal ganglia and substantia nigra(dopaminergic)
• 5-HT1B/1D-cranial blood vessel-constriction (sumatriptan –
selective agonist
11
 5-HT 2 RECEPTOR
• 3 subtypes 5-HT2A,5-HT2B,5-HT2C
• All are coupled to Gq proteinactivate phospho lipase CIP3/DAG
• 5-HT2A
- most widely expressed postjunctional receptor(D-type)
-Located on vascular, visceral smooth muscle, platelets and cerebral neurons
-Mediates direct action of 5-HT like vasoconstriction,intestinal,uterine and
bronchial contraction, platelet aggregation and activation of cerebral
neurons.(ketanserin – selective antagonist)
• 5-HT2C
Vascular endothelium- vasodilatation through EDRF release
Choroid plexus-regulate CSF formation.
12
 5-HT 3 RECEPTOR
• Neuronal 5-HT receptor- depolarization of nerve endings and opening
of channels(m-type)-mediates indirect and reflex effects.
• Somatic and ANS nerve endings – pain , itch, coronary chemo reflex
 fall in BP,bradycardia,respiratory stimulation or apnoea,other visceral reflexes.
• Myenteric plexus nerve endings: augmentation of peristalsis and
emetic reflex
• Brain stem (area postrema and NTS) – nausea, vomiting
• Ondansteron –selective antagonist

13
 5-HT4-7 RECEPTOR
• 5-HT4 Gs type of receptor –activates adenyl cyclase
• Mucosa, plexuses and smooth muscle of gut
• Involved in augmenting intestinal secretions and peristalsis
• In brain hippocampus- slow depolarization of k+ channel
• Cisapride and renzapride –specific agonist
• 5-HT 5,6,7 related to 5-HT4 but their functional role not known

14
15
 ACTIONS OF 5-HT
• Potent depolarizer of nerve endings –exerts direct,reflex,indirect
effects
ON CARDIO VASCULAR SYSTEM:
o Arteries are constricted (direct) as well as dilated (EDRF)-
depends on vascular bed and basal tone
o Also releases Adrenaline –affects ganglionic transmission –CVS
reflexes
o Overall large arteries and veins – constricted but in
microcirculation arterioles(dilate) venules(constrict)capillary 16
pressure and fluid escapes
• Heart: isolated heart stimulation –direct chronotropic and ionotropic
• Intact animal heart :bradycardia due to stimulation of coronary chemo
reflex(Bezold jarisch reflex)- via vagal afferent nerve endings in coronary
bed
- Overall bradycardia, hypotension and apnoea
• Blood pressure:triphasic response on BP
early sharp fall : coronary chemoreflex
brief rise :vasoconstriction and increased CO
prolonged fall : arteriolar dilatation and extravasations of fluid
(not involved in physiological regulation of BP)
17
 Visceral Smooth Muscle
• GIT: stimulator of GIT –direct and through entero chromaffin cells in
mucosa
GIT motility –increased peristalsis and diarrhoea
• Bronchi: constricts
• Glands:5-HT inhibits gastric secretion( acid and pepsin ),but
increases mucus production –ulcer protective property
• Nerve endings and adrenal medulla : afferent nerve endings are
activated –tingling and prickling sensation-also pain

18
 ..
• Respiration : Stimulation –reflex from
bronchial afferents and hyperventilation( large
dose apnoea-coronary chemoreflex)
• Platelets- aggregation 5-HT 2A
• CNS:Poor entry to BBB –however act as
inhibitory NT
 direct inj:hunger,sleepiness,behavioural
changes

19
 PATHOPHYSIOLOGICAL ROLES
• Neurotransmitter :regulates sleep ,temperature
regulation,thought,cognitive,behaviour,mood,appetite,vomiting,
pain perception
• Precursor of melatonin
• Neuroendocrine function
• Nausea and vomiting
• Migraine
• Haemostasis
20
 ..
• Hypertension :reduced uptake and clearance
• Intestinal motility:peristalsis and local reflexes
• Carcinoid syndrome: massive quantity
–bowel hypermotility and bronchoconstriction

21
22
23