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Vol. 55, Issue 2, 339-347, February 1999
Institut de Pharmacologie et de Toxicologie, Faculté de
Médecine, 1005 Lausanne, Switzerland (S.M-K., A.S., L.A., D.D.,
S.C.); and
Howard Hughes Medical Institute, Duke University Medical
Center, Durham, North Carolina (L.S.B., M.G.C.)
We compared the phosphorylation and internalization properties of
constitutively active alpha-1b adrenergic receptor (AR) mutants carrying mutations in two distant receptor domains, i.e., at
A293 in the distal part of the third intracellular loop and at
D142 of the DRY motif lying at the end of the third transmembrane domain. For the A293E and A293I mutants the levels of
agonist-independent phosphorylation were 150% and 50% higher than
those of the wild-type alpha-1b AR, respectively. On the
other hand, for the constitutively active D142A and D142T mutants, the
basal levels of phosphorylation were similar to those of the wild-type
alpha-1b AR and did not appear to be further stimulated
by epinephrine. Overexpression of the guanyl nucleotide binding
regulatory protein-coupled receptor kinase GRK2 further increases the
basal phosphorylation of the A293E mutant, but not that of D142A
mutant. Both the wild-type alpha-1b AR and the A293E
mutant could undergo 
-arrestin-mediated internalization. The
epinephrine-induced internalization of the constitutively active A293E
mutant was significantly higher than that of the wild-type
alpha-1b AR. In contrast, the D142A mutant was impaired
in its ability to interact with -arrestin and to undergo
agonist-induced internalization. Interestingly, a double mutant
A293E/D142A retained very high constitutive activity and regulatory
properties of both the A293E and D142A receptors. These findings
demonstrate that two constitutively activating mutations occurring in
distant receptor domains of the alpha-1b AR have divergent effects on the regulatory properties of the receptor.
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