Receptor activation involving positive allosteric modulation, unlike full agonism, does not result in GABAB receptor desensitization.
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Gjoni, Tina and Urwyler, Stephan (2008) Receptor activation involving positive allosteric modulation, unlike full agonism, does not result in GABAB receptor desensitization. Neuropharmacology, 55 (8). pp. 1293-1299. ISSN 0028-3908
Abstract
Allosteric modulators act more physiologically than orthosteric ligands, targeting only endogenously activated receptors and not their whole population, which is why they are expected to produce less side effects and tolerance. To inspect the role of the positive allosteric modulator GS39783 in GABAB receptor desensitization, we examined receptor function and cell surface expression in a recombinant GABAB cell line and in primary neuronal cultures upon persistent treatments with GABAB agonists, and combinations of agonists and GS39783. The potency of GABA to inhibit 7beta-forskolin-induced cAMP formation in recombinant cells decreased after the exposure to a saturating GABA concentration, but not after a combination of a low GABA concentration and GS39783, that activated the receptor to the same extent. Concordantly, a significant decrease of cell surface receptors was found after GABA-induced desensitization, unlike after the combined treatment with GABA and GS39783. Similar observations regarding receptor function were found in primary neurons for baclofen-induced inhibition of spontaneous Ca2+ oscillations. However, the cell surface receptor density remained unaffected upon baclofen-induced desensitization in the primary neurons, possibly due to different mechanisms of desensitization in the neurons and the recombinant cell line. These findings indicate that the degree of occupancy of the orthosteric site determines desensitization rather than the degree of receptor activation. In summary, our results conform to predictions that positive allosteric modulators have less propensity for the development of tolerance due to receptor desensitization than classical agonists.
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| Keywords: | GABAB receptor; Allosteric modulators; Desensitization; GS39783 |
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| Date Deposited: | 14 Dec 2009 13:48 |
| Last Modified: | 14 Dec 2009 13:48 |
| URI: | https://oak.novartis.com/id/eprint/1467 |