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Vol. 57, Issue 4, 687-694, April 2000
1B-
Adrenergic Receptor
Department of Pharmacology, University of Nebraska Medical Center,
Omaha, Nebraska
The roles of the carboxyl-terminal tail of the
1B-adrenergic receptor in its expression,
function, and regulation were investigated by site-directed
mutagenesis. The receptor construct truncated after residue 363 seemed
not to be properly expressed. In contrast, the receptor truncated after
residue 366 and all of the longer receptor constructs were properly
expressed and exhibited agonist and antagonist binding and activation
of phosphoinositide hydrolysis similar to the wild-type receptor.
Agonist-induced sequestration of receptors within the plasma membrane,
endocytosis into intracellular vesicles, and eventual down-regulation
were all absent in the receptor truncated after residue 366. A series
of sequential truncations and a deletion mutation identified a critical
role for residues 403 to 425, which include the previously identified
sites for G protein-coupled receptor kinase phosphorylation, in
agonist-induced internalization of the receptor. Similar studies
identified a critical role for residues 367 to 380 in agonist-induced
down-regulation. Individual point mutations converting either cysteine
367 or serine 369 to alanine selectively eliminated down-regulation,
thus identifying two specific amino acid residues required for
down-regulation. Importantly, several of the mutated receptors that
failed to show rapid agonist-induced internalization nonetheless
exhibited normal agonist-induced down-regulation. In addition to
identifying specific regions and individual residues of the
1B-adrenergic receptor involved in
internalization and down-regulation, these studies provide mutated
receptors that internalize but do not down-regulate, that down-regulate
without internalization, and that are defective in both internalization
and down-regulation, all of which should be useful tools for further
studies of the specific cellular compartments and molecular mechanisms
involved in receptor internalization and down-regulation.
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