| Autor: |
Salah-Uddin, Hasib, Thomas, David R., Davies, Ceri H., Hagan, Jim J., Wood, Martyn D., Watson, Jeannette M., Challiss, R.A. John |
| Zdroj: |
The Journal of Pharmacology and Experimental Therapeutics; June 2008, Vol. 325 Issue: 3 p869-874, 6p |
| Abstrakt: |
Using a selective Gαq/11protein antibody capture guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding approach, it has been possible to perform a quantitative pharmacological examination of the functional activity of the M1muscarinic acetylcholine receptor (mAChR) in membranes prepared from human postmortem cerebral cortex. Oxotremorine-M caused a ≥2-fold increase in [35S]GTPγS-Gαq/11binding with a pEC50of 6.06 ± 0.16 in Brodmann’s areas 23 and 25 that was almost completely inhibited by preincubation of membranes with the M1mAChR subtype-selective antagonist muscarinic toxin-7. In addition, the orthosteric and allosteric agonists, xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] and AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride), increased [35S]-GTPγS-Gαq/11binding, but with reduced intrinsic activities, inducing maximal responses that were 42 ± 1 and 44 ± 2% of the oxotremorine-M-induced response, respectively. These data indicate that the M1receptor is the predominant mAChR subtype coupling to the Gαq/11G protein in these brain regions and that it is possible to quantify the potency and intrinsic activity of full and partial M1mAChR receptor agonists in postmortem human brain using a selective Gαq/11protein antibody capture [35S]GTPγS binding assay. |
| Databáze: |
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