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Constitutively active mutants of the alpha 2-adrenergic receptor
Ist Teil von
The Journal of biological chemistry, 1993-08, Vol.268 (22), p.16483-16487
Ort / Verlag
United States: American Society for Biochemistry and Molecular Biology
Erscheinungsjahr
1993
Quelle
Electronic Journals Library
Beschreibungen/Notizen
We have mutated a single residue, Thr373 [corrected], in the C-terminal portion of the third intracellular loop of the alpha
2C10-adrenergic receptor into five different amino acids. In analogy with the effect of similar mutations in the alpha 1B-
and beta 2-adrenergic receptors, these substitutions resulted in two major biochemical modifications: 1) increased constitutive
activity of the alpha 2-adrenergic receptor leading to agonist-independent inhibition of adenylyl cyclase and 2) increased
affinity of the receptor for binding agonist but not antagonists. The increased constitutive activity of the mutated alpha
2-adrenergic receptors could be inhibited by pertussis toxin, clearly indicating that it results from spontaneous ligand-independent
receptor coupling to Gi. In contrast, the increased affinity of the mutant receptors for binding agonists was unaffected by
pertussis toxin treatment, indicating that this is an inherent property of the receptors not dependent on interaction with
Gi. Coexpression of the receptor mutants with the receptor-specific kinase, beta ARK1, indicated that the constitutively active
alpha 2-adrenergic receptors are substrates for beta-adrenergic receptor kinase (beta ARK)-mediated phosphorylation even in
the absence of agonist. These findings strengthen the idea that constitutively active adrenergic receptors mimic the "active"
state of a G protein-coupled receptor adopting conformations similar to those induced by agonist when it binds to wild type
receptors. In addition, these results extend the notion that in the adrenergic receptor family the C-terminal portion of the
third intracellular loop plays a general role in the processes involved in receptor activation.