1. Serotonin (5HT) Receptor subtypes SubtypeSignal transduction LocalizationFunctionSelective Agonist Selective Antagonist 5-HT 1A Inhibition of AC HippocampusAutoreceptor 8-OA-DPATWAY 100135 5-HT 1B Inhibition of AC Substantia nigraAutoreceptor -- 5-HT 1D Inhibition of AC Cranial blood vesselsVasoconstriction Sumatriptan- 5-HT 1E Inhibition of AC Cortex- -- 5-HT 1F Inhibition of AC Brain, Periphery- -- 5-HT 2A Activation of PLC Platelet, smooth muscle, cerebral cortex Platelet aggre n, Contra n, Neuronal excitation DOIKetanserin, Resperidone 5-HT 2B (D- receptor) Activation of PLC Stomach fundusContraction DOILY53857 5-HT 2C Activation of PLC Choroid plexus- DOILY53857, Mesulergine 5-HT 3 (M-receptor) Ion channel PNSNeuronal excitat n 2-methyl- 5HT Ondansetron, Tropisetron 5-HT 4 Activation of AC GI tract, HippocampusNeuronal excitat n RenzaprideGR113808 5-HT 5A Inhibition of AC HippocampusUnknown --- 5-HT 5B Unknown - -- 5-HT 6 Activation of AC StriatumUnknown -- 5-HT 7 Activation of AC Hypothalamus, IntestineUnknown --

2. Sites of 5HT action Stored and secreted by -- Enterochromaffin-like (ECL) cell of GI mucosa --Platelets □ ECL cells synthesize 5HT from tryptophan and store 5HT and other autacoids (substance P, kinins) □ Platelets don’t synthesize 5HT but take up from circulation by active transport to store in secretory granules

3. Sites of 5HT action ECL Cells: Basal release of 5HT augmented by mechanical stretching (like caused by intake of food or hypertonic saline).Also has GI motility stimulation effect. Clinical implication: Synthesis in large amount by carcinoid tumors result in tryptophan deficiency (pellagra)

4. Sites of 5HT action Platelets: Platelets when make contact with injured endothelium, release substances (thrombin, thromboxane A 2 ) that promote platelet adhesion and release of 5HT. Then 5HT on binding to 5-HT 2A receptors elicit weak aggregation response [markedly enhanced in presence of collagen]. 5HT also exerts a direct constrictor effect, promoting hemostatis [locally released kinins, thromboxane A 2 enhance this action]

5. Sites of 5HT action CVS system: Classical response is vasoconstriction [in renal, pulmonary and cerebral vasculatures] Has positive inotropic and chronotropic effect on heart Clinical implication: sometimes may cause extreme bradycardia (slow heart rate) and hypotension

6. Sites of 5HT action [in GI tract] GI tract SiteResponseReceptor ECL cellsRelease of 5HT, Inhibition of 5HT release (autoreceptor) 5HT 3,5HT 4 Enteric ganglionic cells (presynaptic) Release of Ach, Inhibition of Ach release (autoreceptor) 5HT 4, 5HT 1A Enteric ganglionic cells (postsynaptic) Fast depolarization5HT 3 Smooth muscle [intestinal] Contraction5HT 2A Smooth muscle [stomach fundus] Contraction5HR 2B Smooth muscle [esophagus] Contraction5HT 4

7. Sites of 5HT action [in GI tract] In esophagus, 5HT acting on 5HT4 receptors causes either relaxation or contraction, depending on species 5HT3 receptor activation on vagal and other afferent neurons causes emesis Clinical implication: 5HT3 antagonists [Ondansetron] used as anti-emetic Local Effect: Release of enteric 5HT in response to Ach increases intra-luminal pressure and trigger peristaltic contraction

8. Sites of 5HT action CNS: sleep, cognition, motor activity, sensory perception, nociception and temperature regulation are influenced by 5HT Clinical implication: 5HT antagonists are typical antipsychotics

12. Ref: Goodmann & Gilmann