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Vol. 57, Issue 2, 219-231, February 2000
1b-Adrenergic Receptor:
Effects on Receptor Isomerization and Activation
Institut de Pharmacologie et Toxicologie, Université de
Lausanne, Lausanne, Switzerland (A.S., S.M.-K., L.A., M.N.-T., S.C.);
Istituto Superiore di Sanità, Roma, Italy (T.C.); and
Dipartimento di Chimica, Università di Modena e Reggio Emilia,
Modena, Italy (F.F., P.G.D.B.).
We have suggested previously that both the negatively and positively
charged residues of the highly conserved Glu/Asp-Arg-Tyr (E/DRY) motif
play an important role in the activation process of the
1b-adreneric receptor (AR). In this study, R143 of the E/DRY sequence in the 1b-AR was mutated into several
amino acids (Lys, His, Glu, Asp, Ala, Asn, and Ile). The
charge-conserving mutation of R143 into lysine not only preserved the
maximal agonist-induced response of the 1b-AR, but it
also conferred high degree of constitutive activity to the receptor.
Both basal and agonist-induced phosphorylation levels were
significantly increased for the R143K mutant compared with those of the
wild-type receptor. Other substitutions of R143 resulted in receptor
mutants with either a small increase in constitutive activity (R143H
and R143D), impairment (R143H, R143D), or complete loss of
receptor-mediated response (R143E, R143A, R143N, R143I). The R413E
mutant displayed a small, but significant increase in basal
phosphorylation despite being severely impaired in receptor-mediated response. Interestingly, all the arginine mutants displayed increased affinity for agonist binding compared with the wild-type
1b-AR. A correlation was found between the extent of the
affinity shift and the intrinsic activity of the agonists. The analysis
of the receptor mutants using the allosteric ternary complex model in conjunction with the results of molecular dynamics simulations on the
receptor models support the hypothesis that mutations of R143 can drive
the isomerization of the 1b-AR into different states,
highlighting the crucial role of this residue in the activation process
of the receptor.
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