Partial to complete antagonism by putative antagonists at the wild-type α(2C)-adrenoceptor based on kinetic analyses of agonist : antagonist interactions

1. Activation of the recombinant human α(2C)-adrenoceptor (α(2C) AR) by (−)-adrenaline in CHO-K1 cells transiently co-expressing a chimeric G(αq/i1) protein induced a rapid, transient Ca(2+) response with a high-magnitude followed by a low-magnitude phase which continued throughout the recorded time period (15 min). 2. Activation of the α(2C) AR by various α(2) AR agonists revealed the following rank order of high-magnitude Ca(2+) response [E(max) (%) versus 10 μM (−)-adrenaline]: UK 14304 (102±4)=talipexole (101±3)=(−)-adrenaline (100)=d-medetomidine (98±1)>oxymetazoline (81±4)⋍clonidine (75±5). 3. The methoxy- (RX 821002) and ethoxy-derivatives (RX 811059) of idazoxan and the dexefaroxan analogue atipamezole were fully effective as antagonists of both the high- and the low-magnitude Ca(2+) response. However, though acting as full antagonists of the high-magnitude response, the further putative α(2) AR antagonists idazoxan (27%), SKF 86466 (29%) and dexefaroxan (59%) reversed the low-magnitude response only partially. 4. In conclusion, kinetic analyses of agonist : antagonist interactions at the α(2C) AR demonstrate a wide spectrum of partial to complete antagonism of the low-magnitude Ca(2+) response for structurally related α(2) AR ligands

Short-term Disappearance of Muscarinic Cell-surface Receptors in Carbachol-induced Desensitization

AbstractA rapid carbachol-induced disappearance of muscarinic cell surface receptors was shown using [3H]methyl scopolamine as ligand on intact 108CC15 hybrid cells or rat cerebellar cells. This phenomenon is temperature-dependent, correlated to agonist stimulation and reversible. In these short time periods (⩽30 min), no change was observed in the total receptor amount measured on membrane preparations. This disappearance of cell surface receptors could represent the first event in cell desensitization which could be followed by receptor recycling in physiological conditions or by receptor degradation if the stimulation by agonists persists, as in long-term regulation