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Volume 272, Number 24, Issue of June 13, 1997 pp. 15466-15473
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

The 3-Untranslated Region of the _2C-Adrenergic Receptor mRNA Impedes Translation of the Receptor Message

(Received for publication, February 6, 1997, and in revised form, March 24, 1997)

Qing Yang , Paul J. McDermott ^§ , Emir Duzic , Cornelius W. A. Pleij , John D. Sherlock and Stephen M. Lanier

From the Department of Pharmacology, ^§ Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425 and  Leiden Institute of Chemistry, Leiden University, 2300 RA Leiden, The Netherlands

We report that two subtypes of ₂-adrenergic receptors (_2A/D- and _2C-AR) are ectopically expressed with dramatically different efficiencies and that this difference is due to a 288-nucleotide (nt) segment in the 3-untranslated region (3-UTR) of the _2C-AR mRNA that impairs translational processing. NIH-3T3 fibroblasts were transfected with receptor constructs (coding region plus 552 nt, _2C-AR; coding region plus 1140 nt, _2A/D-AR) and a vector conferring G418 resistance. Transcription was driven by the murine sarcoma virus promoter element, and the receptor gene segment was upstream of an SV40 polyadenylation cassette. Drug-resistant transfectants were evaluated for expression of receptor mRNA and protein. 90% of the NIH-3T3 _2C-AR transfectants expressed receptor mRNA, but only 14% of the clonal cell lines expressed receptor protein. In contrast, 90% of the NIH-3T3 _2A/D-AR transfectants expressed receptor protein (200-5000 fmol/mg). Similar results were obtained following transfection of DDT₁MF-2 cells with the two receptor constructs. The role of the 3-UTR of the _2C-AR in mRNA processing was determined by generating new constructs in which the 3-UTR was progressively truncated from 552 to 470, 182, 143, or 74 nt 3 to the stop codon. Truncation of the 3-UTR resulted in the expression of receptor protein in the G418-resistant transfectants (nt 74, 100%; nt 143, 80%; nt 182, 50%). The level of mRNA in the transfectants expressing the receptor protein was not greater than that in nonexpressing clones, and the differences in protein expression did not reflect altered mRNA stability in the truncated construct. The _2C-AR mRNA with the longer 3-UTR underwent translational initiation as it was found in the polysome fraction, indicating that the lack of receptor protein was due to impaired translational elongation or termination. These data suggest that translational efficiency is a key mechanism for regulating _2C-AR expression and associated signaling events.

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