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Vol. 57, Issue 5, 890-898, May 2000
Leiden/Amsterdam Center for Drug Research, Medicinal Chemistry,
Division of Chemistry, Faculty of Sciences, Vrije Universiteit, De
Boelelaan, HV Amsterdam, The Netherlands (A.E.A., H.T., E.H.J., M.J.S.,
E.R., R.L.); and Institut de Pharmacologie et Toxicologie,
Université de Lausanne, Lausanne, Switzerland (S.C.)
In previous studies we showed that the wild-type histamine
H2 receptor stably expressed in Chinese hamster ovary cells
is constitutively active. Because constitutive activity of the
H2 receptor is already found at low expression levels (300 fmol/mg protein) this receptor is a relatively unique member of the
G-protein-coupled receptor (GPCR) family and a useful tool for studying
GPCR activation. In this study the role of the highly conserved DRY
motif in activation of the H2 receptor was investigated.
Mutation of the aspartate 115 residue in this motif resulted in
H2 receptors with high constitutive activity, increased
agonist affinity, and increased signaling properties. In addition, the
mutant receptors were shown to be highly structurally instable.
Mutation of the arginine 116 residue in the DRY motif resulted also in
a highly structurally instable receptor; expression of the receptor
could only be detected after stabilization with either an agonist or
inverse agonist. Moreover, the agonist affinity at the Arg-116
mutant receptors was increased, whereas the signal transduction
properties of these receptors were decreased. We conclude that the
Arg-116 mutant receptors can adopt an active conformation but have a
decreased ability to couple to or activate the Gs-protein.
This study examines the pivotal role of the aspartate and arginine
residues of the DRY motif in GPCR function. Disruption of receptor
stabilizing constraints by mutation in the DRY motif leads to the
formation of active GPCR conformations, but concomitantly to GPCR instability.
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