RT Journal Article
SR Electronic
T1 Phenylalanine 169 in the Second Extracellular Loop of the Human Histamine H<sub>4</sub> Receptor Is Responsible for the Difference in Agonist Binding between Human and Mouse H<sub>4</sub> Receptors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 88
OP 96
DO 10.1124/jpet.108.140343
VO 327
IS 1
A1 Herman D. Lim
A1 Aldo Jongejan
A1 Remko A. Bakker
A1 Eric Haaksma
A1 Iwan J. P. de Esch
A1 Rob Leurs
YR 2008
UL http://jpet.aspetjournals.org/content/327/1/88.abstract
AB Using the natural variation in histamine H4 receptor protein sequence, we tried to identify amino acids involved in the binding of H4 receptor agonists. To this end, we constructed a variety of chimeric human-mouse H4 receptor proteins to localize the domain responsible for the observed pharmacological differences between human and mouse H4 receptors in the binding of H4 receptor agonists, such as histamine, clozapine, and VUF 8430 [S-(2-guanidylethyl)-isothiourea]. After identification of a domain between the top of transmembrane domain 4 and the top of transmembrane domain 5 as being responsible for the differences in agonist affinity between human and mouse H4Rs, detailed site-directed mutagenesis studies were performed. These studies identified Phe169 in the second extracellular loop as the single amino acid responsible for the differences in agonist affinity between the human and mouse H4Rs. Phe169 is part of a Phe-Phe motif, which is also present in the recently crystallized β2-adrenergic receptor. These results point to an important role of the second extracellular loop in the agonist binding to the H4 receptor and provide a molecular explanation for the species difference between human and mouse H4 receptors. The American Society for Pharmacology and Experimental Therapeutics