HUMAN MUSCARINIC RECEPTORS EXPRESSED IN A9L AND CHO CELLS - ACTIVATION BY FULL AND PARTIAL AGONISTS

1 A comparative study of receptor activation by ten full and partial m uscarinic agonists was undertaken on the five subtypes of human muscar inic receptors expressed at similar receptor densities in Chinese hams ter ovary (CHO-K1) cells. In addition, m(1), m(2) and m(3) receptors w ere expressed in mouse fibroblast A9L cells in order to compare the in fluences of cell type on agonist activation of these receptors. 2 Rece ptor-effector coupling efficiencies were greater in CHO than A9L cells and agonists displayed greater potencies and similar or greater intri nsic activities at CHOm(1) and CHOm(3) than A9Lm(1) and A9Lm(3) recept ors. Although mt receptor density was 6 fold higher in A9L than CHO ce lls, carbachol elicited significantly greater inhibition of adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation in CHOm(2) cells. Th ese data suggest that not only receptor density but receptor-effector coupling and/or coupling efficiencies play significant roles in agonis t-induced responses. 3 In CHO cells, receptor-effector coupling effici encies were m(3)=m(1)>m(5). Although CHOm(5) receptors were the least efficiently coupled, some partial agonists displayed higher intrinsic efficacies at m(5) than m(3) receptors suggesting that, in CHO cells, m(5) and m(3) receptors may activate different G proteins and/or effec ters to stimulate inositol monophosphate (IP1) formation. 4 McN-A-343 was a functionally selective m(4) agonist. It had little or no agonist activity at m(3) receptors expressed in either A9L or CHO cells. The slopes of McN-A-343 concentration-response curves in CHOm(2) cells wer e significantly lower than the slopes obtained with this compound in C HOm(4) cells suggesting that the mode of activation by McN-A-343 diffe red between the two muscarinic receptors negatively coupled to adenyly l cyclase. 5 Cloned receptors provide valuable tools for the study of agonist-receptor interaction and agonist-receptor activation but cauti on should be applied in assuming that the results are valid for all ce ll types or for tissue-expressed receptors.