Regulation of heterologously expressed 5-HT1Breceptors coupling to potassium channels in AtT-20 cells
| Autor: | Chris Bladen, Marika Heblinski, Mark Connor |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pharmacology Agonist medicine.drug_class Chemistry medicine.medical_treatment Potassium channel Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine Staurosporine Serotonin G protein-coupled inwardly-rectifying potassium channel Receptor 030217 neurology & neurosurgery Desensitization (medicine) medicine.drug G protein-coupled receptor |
| Zdroj: | British Journal of Pharmacology. 176:451-465 |
| ISSN: | 0007-1188 |
| Popis: | Background and purpose 5-HT1B receptors are widely expressed GPCRs and a target of triptans, the most commonly prescribed anti-migraine drugs. There is very limited information about the acute, agonist-induced regulation of 5-HT1B receptor signalling and so we sought to characterize this in a neuron-like system. Experimental approach Epitope-tagged human 5-HT1B receptors were expressed in mouse AtT20 cells. 5-HT1B receptor signalling was assessed using whole-cell patch-clamp recordings of endogenous G protein-gated inwardly rectified potassium (GIRK) channels, and receptor localization measured using immunofluorescence. Key results 5-HT (EC50 65 nM) and sumatriptan (EC50 165 nM) activated GIRK channels in AtT20 cells expressing 5-HT1B receptors. Continuous application of both 5-HT (EC50 120 nM) and sumatriptan (EC50 280 nM) produced profound desensitization of 5-HT1B receptor signalling within a few minutes. Complete recovery from desensitization was observed after 10 min. Both 5-HT and sumatriptan induced significant heterologous desensitization of SRIF (somatostatin)-activated GIRK currents, with the 5-HT-induced heterologous desensitization being blocked by the protein kinase inhibitor staurosporine. Both agonists induced modest 5-HT1B receptor internalization, with a time course much slower than receptor desensitization. Conclusions and implications In AtT-20 cells, 5-HT1B receptors undergo rapid and reversible desensitization at concentrations of agonist similar to those required to activate the receptor. Desensitization is incomplete, and the continued signalling of the receptor in the presence of the agonist may lead to cellular adaptations. Finally, 5-HT1B receptor activation causes significant heterologous desensitization, which may lead to a reduced effectiveness of unrelated drugs in vivo. |
| Databáze: | OpenAIRE |
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