Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 304, Issue 1, Pages 229-237Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.102.042184
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Funding
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA002189, R56DA002189] Funding Source: NIH RePORTER
- NIDA NIH HHS [DA02189] Funding Source: Medline
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NIH3T3 cells stably expressing the rat 5-hydroxytryptamine(2A) (5-HT2A) receptor (5500 fmol/mg) were used to explore further the capacity of structurally distinct ligands to elicit differential signaling through the phospholipase C (PLC) or phospholipase A(2) (PLA(2)) signal transduction pathways. Initial experiments were designed to verify that 5-HT2A receptor-mediated PLA(2) activation in NIH3T3 cells is independent from, and not a subsequent result of, 5-HT2A receptor-mediated PLC activation. In addition, we also explored the extent of receptor reserve for the endogenous ligand, 5-HT, for both PLC and PLA(2) activation. Finally, we employed structurally diverse ligands from the tryptamine, phenethylamine, and ergoline families of 5-HT2A receptor agonists to test the hypothesis of agonist-directed trafficking of 5-HT2A receptor-mediated PLC and PLA(2) activation. To measure agonist-induced pathway activation, we determined the potency and intrinsic activity of each compound to activate either the PLA(2) pathway or the PLC pathway. The results showed that a larger receptor reserve exists for 5-HT-induced PLA(2) activation than for 5-HT-induced PLC activation. Furthermore, the data support the hypothesis of agonist-directed trafficking in NIH3T3-5HT(2A) cells because structurally distinct ligands were able to induce preferential activation of the PLC or PLA(2) signaling pathway. From these data we conclude that structurally distinct ligands can differentially regulate 5-HT2A receptor signal transduction.
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