Click to download
Catecholamine And Secondary Site Responses Remain Unaffected By The Polymorphic Variants Of The Human β1-adrenoceptor The human β1-adrenoceptor exists in two different agonist conformations. Classical agonists stimulate the catecholamine conformation, CGP 12177 stimulates the secondary conformation and several ligands activate both agonist conformations (Baker 2010). The human β1-adrenoceptor also has two polymorphic variants. Previous studies suggest that whilst catecholamine responses are greater in the Arg389 receptor, CGP 12177 responses are greatly reduced in the Arg389 compared to the Gly389 receptor due to poor Arg389 secondary site Gs-coupling (Joseph 2004).This study examined functional responses to the wild type and polymorphic receptors stably expressed in CHO-K1 cells, using 3H-cAMP accumulation as previously described (Baker 2010). Cimaterol and CGP 12177 stimulated responses at all 3 receptors that were inhibited by β-antagonists see table1. Inhibition of CGP 12177 responses required higher concentrations of antagonist in keeping with secondary site activation, however these responses were substantial at all 3 receptors. Furthermore, ligands stimulating both agonist conformations did so at all 3 receptors and the proportion of agonism at each conformation remained the same table 2.
Table 1. log EC50 values and % maximum isoprenaline response for cimaterol and CGP 12177 and log KD values for antagonism of these responses by bisoprolol and carvedilol. Values are mean ±s.e.m.
Table 2. log EC50 values at the two sites, % response at each site and total maximal response for pindolol at the 3 receptors. Values are mean ± s.e.m. of n separate experiments. This study suggests that both polymorphic variants of the human β1-adrenoceptor possess the two agonist conformations seen in the wild type receptor. Furthermore, catecholamine and secondary site responses at all 3 receptors are proportionally similar suggesting that in both position 49 and 389 polymorphic variants of the receptor, the coupling to Gs-proteins is not affected.
Baker JG (2010) Brit J Pharmacol 160: 1048-1061 Joseph SS et al., (2004) Brit J Pharmacol 142: 51-56
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
