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Signal transduction differences between 5-hydroxytryptamine type 2A and type 2C receptor systems
K A Berg1, W P Clarke, C Sailstad
1Department of Anesthesiology, Mount Sinai School of Medicine, City University of New York, New York 10029.
Abstract:
The cDNAs for human 5-hydroxytryptamine (5-HT)2C and 5-HT2A receptors were stably transfected separately into parent Chinese hamster ovary cells, and cell lines in which levels of transfected receptor protein expression and accumulation of inositol phosphates in response to 5-HT were comparable were chosen for study. The effect of activation of these receptors on 5-HT1B-like receptor-mediated responsiveness (i.e., inhibition of forskolin-stimulated cAMP accumulation) was studied. Activation of 5-HT2C receptors with 5-HT (0.1-100 microM) abolished the 5-HT1B-like response, which returned when 5-HT2C receptors were blocked with mesulergine (1 microM). Furthermore, the maximal response to 5-carboxytryptamine was reduced in a concentration-dependent manner by the 5-HT2A/5-HT2C-selective partial agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. In contrast, activation of 5-HT2A receptors with either 5-HT or (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane did not alter the 5-HT1B-like response. The reduction of 5-HT1B-like responsiveness produced by 5-HT2C receptor activation was independent of protein kinase C activation and increases in the intracellular calcium concentration. Although 5-HT2A and 5-HT2C receptors are strikingly similar in structure and pharmacology, and the signal transduction systems coupled to these receptors have been thought to be similar, if not identical, these data provide the first evidence for fundamental differences in the signal transduction systems of these 5-HT2 receptor subtypes.
Insights
The 5-hydroxytryptamine (5-HT)2C receptor, but not the 5-HT2A receptor, significantly inhibits 5-HT1B-like signaling. This finding reveals distinct signal transduction pathways for these related serotonin receptors.
Area of Science:
- Neuroscience
- Molecular Pharmacology
- Cell Signaling
Background:
- Human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors share structural and pharmacological similarities.
- The signal transduction pathways for 5-HT2A and 5-HT2C receptors are presumed to be identical.
- Understanding receptor-specific signaling is crucial for developing targeted therapeutics.
Purpose of the Study:
- To investigate the differential effects of 5-HT2A and 5-HT2C receptor activation on 5-HT1B-like receptor-mediated signaling.
- To elucidate the signal transduction mechanisms underlying 5-HT2 receptor subtype function.
Main Methods:
- Stable transfection of human 5-HT2A and 5-HT2C receptor cDNAs into Chinese hamster ovary cells.
- Assessment of 5-HT1B-like receptor-mediated inhibition of forskolin-stimulated cAMP accumulation.
- Pharmacological characterization using selective agonists and antagonists.
Main Results:
- Activation of 5-HT2C receptors abolished 5-HT1B-like signaling, an effect reversed by mesulergine.
- The 5-HT2A/5-HT2C-selective agonist reduced 5-HT1B-like responses in a concentration-dependent manner.
- Activation of 5-HT2A receptors did not affect 5-HT1B-like signaling.
- 5-HT2C-mediated inhibition was independent of protein kinase C and intracellular calcium.
Conclusions:
- This study provides the first evidence for fundamental differences in the signal transduction pathways of 5-HT2A and 5-HT2C receptor subtypes.
- The 5-HT2C receptor actively modulates 5-HT1B-like signaling, while the 5-HT2A receptor does not.
- These findings have significant implications for understanding serotonin receptor function and drug development.