So what is there to learn about the role of serine residues in the transmembrane segment 5 (TM5) of biogenic amine receptors that has not already been studied two decades ago by the Strader group? The investigations of Cummings et al. provide interesting structural insight into the binding of dopamine, norepinephrine, and Ro10-4548 [RAC-2′-2-hydroxy-3-4-(4-hydroxy-2-methoxyphenyl)-1-piperazinyl-propoxy-acetanilide] to the D4 dopamine receptor. Systematic serine to alanine mutations of the TM5 serines were used to alter the affinity of ligands to the D4 dopamine receptor in binding and functional assays. Mutation of any of the TM5 serines dramatically reduced functional dopamine and norepinephrine activation of the D4 receptor, in contrast to D2 and D3 receptors where mutations at S5.42 and S5.46 had no effect on activation. This study is the first report of a single point mutation in a dopamine receptor, D4-S5.43A, which converts a specific and highly selective ligand, Ro10-4548, from an antagonist to an agonist. The experimental and modeling data presented in these studies suggest that the preferred mode of interaction between the catechol or catechol-like moieties with the conserved serines of TM5 determines the catechol-like agonists' specific tendencies to elicit a functional response at the D4 dopamine receptor and thus tunes the efficacy observed for these ligands.
See article at J Pharmacol Exp Ther 2010, 333:682–695.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics