Influence of receptor number on the stimulation by salmeterol of gene transcription in CHO‐K1 cells transfected with the human β2‐adrenoceptor

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Abstract
The β2-agonist salmeterol is a potent relaxant of airway smooth muscle with a long duration of action. Previous studies of cyclic AMP accumulation, however, have indicated that salmeterol is a low efficacy β2-agonist when compared to isoprenaline. Here we have compared the properties of salmeterol and isoprenaline as stimulants of gene transcription in CHO-K1 cells transfected with the human β2-adrenoceptor to different levels (50 and 310 fmol mg protein−1).Gene transcription was monitored using a secreted placental alkaline phosphate (SPAP) reporter gene under the transcriptional control of six cyclic AMP response element (CRE) sequences.In the lower expressing cells (CHO-β2/6), salmeterol produced a maximal cyclic AMP response that was only 22% that of that obtained with isoprenaline. In contrast in the higher expressing cells (CHO-β2/4), the two maxima were of similar magnitude.Salmeterol was a more potent stimulant of gene transcription, producing the same maximal response as isoprenaline in both cell lines. Furthermore, in the CHO-β2/4 cells, Salmeterol was 50 fold more potent as a stimulant of SPAP secretion than of cyclic AMP accumulation. In contrast, isoprenaline was 24 fold less sensitive as a stimulant of SPAP secretion than of cyclic AMP accumulation. In the presence of serum (10%), the effects of both salmeterol and isoprenaline on gene transcription were augmented.These data suggest that the low efficacy and/or long duration of action of salmeterol, favours a potent stimulation of gene transcription when compared to more efficacious but shorter-lived agonists such as isoprenaline.

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