Pharmacology of the putative M4 muscarinic receptor mediating Ca-current inhibition in neuroblastoma x glioma hybrid (NG 108-15) cells.
1. We have assessed the potency of a range of agonists and antagonists on the muscarinic receptor responsible for inhibiting the Ca-current (ICa) in NG 108-15 hybrid cells. 2. Acetylcholine (ACh), oxotremorine-M and carbachol were potent 'full' agonists (EC50 values were 0.11 microM, 0.14 microM and 2 microM, respectively). Maximum inhibition of peak high-threshold ICa by these agonists was 39.5%. (+/-)-Muscarine, methylfurmethide and arecaidine propargyl ester (APE) were 'partial' agonists, with EC50 values of 0.54 microM, 0.84 microM and 0.1 microM, respectively. 3. Atropine, pirenzepine and himbacine were potent antagonists of muscarinic inhibition of ICa, with apparent pKB values of 9.8, 7.74 and 8.83, respectively. Methoctramine was relatively weak (pKB = 7.63). Atropine and pirenzepine depressed maximum responses to agonists, probably because these antagonists have relatively slow dissociation rates. 4. The characteristic pharmacological profile found for the M4 receptors in these functional experiments (himbacine high affinity, pirenzepine moderate to high affinity, methoctramine low affinity) corresponds well with data from earlier binding experiments (Lazareno et al., 1990). Since mRNA hybridising to probes for the m4 receptor genotype can be detected in these cells, it is suggested that these pharmacological characteristics identify the equivalent expressed receptor subtype M4.
Caulfield
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Department of Pharmacology, University College London.
Brown
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DA
D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects / Q000378:metabolism; D009423:Nervous System Neoplasms / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism*; D010276:Parasympatholytics / Q000494:pharmacology*; D010277:Parasympathomimetics / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D010276:Parasympatholytics; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic