Agonist induced-phosphorylation of Galpha11 protein reduces coupling to 5-HT2A receptors.
Ju Shi, Katerina J Damjanoska, Rakesh K Singh, Gonzalo A Carrasco, Francisca Garcia, Angela J Grippo, Michelle Landry, Nicole R Sullivan, George Battaglia, Nancy A Muma
Journal of Pharmacology and Experimental Therapeutics October 2007 DOI: 10.1124/jpet.107.122317 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic science cell and animal study Peer reviewed |
|---|---|
| Population | A1A1v cells and rats |
| Intervention | DOI |
| Dose | 1 mg/kg/day |
| Duration | 24 h in cells; 1 to 7 days in rats |
| Measures | [125I](+/-)-DOI binding, [3H]ketanserin binding, GTPgammaS-sensitive [125I](+/-)-DOI binding, phospholipase C activity |
| Topics | Serotonin |
| Key points | The authors report that DOI treatment down-regulates 5-HT2A receptors in cells and that phosphorylation of Galpha11 at serine 154 reduces receptor-G protein coupling. In rats, seven days of DOI decreased serotonin-stimulated phospholipase C activity by 40% and increased Galphaq/11 phosphorylation by 51%, which the authors suggest could contribute to desensitization of 5-HT2A receptors. |
Abstract
We previously demonstrated that 24-h treatment with (-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) causes phosphorylation of Galpha11 protein at serine 154 and that this phosphorylation causes desensitization of serotonin (5-HT) 2A receptor signaling in A1A1v cells (Shi et al., 2007). We now report that treatment of A1A1v cells with DOI for 24 h produces a greater reduction in the Bmax of [125I](+/-)-DOI-labeled high-affinity binding sites (46%) than the reduction of [3H]ketanserin binding sites (25%). Although the KD values are not altered, there is a smaller amount of GTPgammaS [guanosine 5'-3-O-(thio)triphosphate]-sensitive [125I](+/-)-DOI binding in DOI-treated cells. These results suggest that DOI treatment causes down-regulation of 5-HT2A receptors and reductions in G protein-coupled 5-HT2A receptors. In contrast, in cells transfected with the phosphorylation state mimic G(alpha11)S154D, GTPgammaS-sensitive [125I](+/-)-DOI binding was decreased by 48%; however, there was no significant difference in the KD and Bmax values of [125I](+/-)-DOI-labeled receptors. The receptor binding experiments suggest that phosphorylation of Galpha11 on serine 154 reduces coupling of 5-HT2A receptors, whereas DOI causes down-regulation of 5-HT2A receptors in addition to the phosphorylation-induced uncoupling of Galpha11 to 5-HT2A receptors. To determine whether DOI increases phosphorylation of Galphaq/11 protein in vivo, rats were treated with 1 mg/kg/day DOI or saline for 1 to 7 days. Seven days of DOI treatment significantly decreased phospholipase C activity stimulated by an Emax concentration of 5-HT by 40% and increased phosphorylation of Galphaq/11 proteins by 51% in the frontal cortex. These data suggest that DOI causes phosphorylation of Galphaq/11 in vivo and could thereby contribute to the desensitization of 5-HT2A receptors.
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