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Research ArticleArticle

Alternative Translation Initiation of Human Regulators of G-Protein Signaling-2 Yields a Set of Functionally Distinct Proteins

Steven Gu, Annepa Anton, Samina Salim, Kendall J. Blumer, Carmen W. Dessauer and Scott P. Heximer
Molecular Pharmacology January 2008, 73 (1) 1-11; DOI: https://doi.org/10.1124/mol.107.036285
Steven Gu
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Annepa Anton
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Samina Salim
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Kendall J. Blumer
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Carmen W. Dessauer
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Scott P. Heximer
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Abstract

The regulator of G-protein signaling (RGS2) contains a characteristic RGS domain flanked by short amino and carboxyl terminal sequences. The RGS domain mediates inhibition of Gαq and Gαi signaling, whereas the amino terminal domain (NTD) directs interaction with adenylyl cyclases, G-protein-coupled receptors, and other signaling partners. Here, we identify a set of novel RGS2 protein products that differ with respect to their amino terminal architecture and functional characteristics. An RGS2 expression reporter cassette revealed four distinct open reading frames (ORFs) that can be expressed from the RGS2 NTD. We hypothesized that alternative translation initiation from four AUG codons corresponding to amino acid positions 1, 5, 16, and 33 could produce the observed RGS2 expression profile. Selective disruption of each AUG confirmed that alternate sites of translation initiation accounted for each of the observed products. Proteins derived from ORFs 1 to 4 showed no difference in Gαq inhibitory potential or recruitment from the nucleus in response to Gαq signaling. By contrast, RGS2 products initiating from methionines at positions 16 (ORF3) and 33 (ORF4) were impaired as inhibitors of type V adenylyl cyclase (ACV) compared with full-length RGS2. We predicted that regulation of the RGS2 expression profile would allow cells to adapt to changing signaling conditions. Consistent with this model, activation of Gαs/ACV but not Gαq signaling increased the relative abundance of the full-length RGS2 protein, suggesting that alternative translation initiation of RGS2 is part of a novel negative feedback control pathway for adenylyl cyclase signaling.

Footnotes

  • This work was supported by grants from the Ontario Heart and Stroke Foundation (NA 5291 to S.P.H.), Parkinson's Disease Society of Canada (Pilot Grant Program to S.P.H.), Canada Research Chairs Program of the Canadian Institute for Health Research (to S.P.H.), the National Institutes of Health (GM60419 to C.W.D. and GM44592 to K.J.B.), and Pfizer/Washington University Biomedical Research Agreement (to K.J.B.).

  • ABBREVIATIONS: RGS, regulator of G-protein signaling; GAP, GTPase activating protein; AC, adenylyl cyclase; ACV, type V adenylyl cyclase; NTD, amino terminal domain; NT, amino terminus; ORF, open reading frame; GFP, green fluorescent protein; ROI, region of interest; IBMX, 3-isobutyl-1-methylxanthine; TMRM, tetramethyl rhodamine methyl ester; RFU, relative fluorescent unit; AM, acetoxymethyl ester; EGFP, enhanced green fluorescent protein; wt, wild type; HEK, human embryonic kidney; FR, fluorescence ratio; IPx, inositol phosphate; kz, Kozak; MG132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received March 22, 2007.
    • Accepted September 10, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (1)
Molecular Pharmacology
Vol. 73, Issue 1
1 Jan 2008
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Research ArticleArticle

Alternative Translation Initiation of Human Regulators of G-Protein Signaling-2 Yields a Set of Functionally Distinct Proteins

Steven Gu, Annepa Anton, Samina Salim, Kendall J. Blumer, Carmen W. Dessauer and Scott P. Heximer
Molecular Pharmacology January 1, 2008, 73 (1) 1-11; DOI: https://doi.org/10.1124/mol.107.036285

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Research ArticleArticle

Alternative Translation Initiation of Human Regulators of G-Protein Signaling-2 Yields a Set of Functionally Distinct Proteins

Steven Gu, Annepa Anton, Samina Salim, Kendall J. Blumer, Carmen W. Dessauer and Scott P. Heximer
Molecular Pharmacology January 1, 2008, 73 (1) 1-11; DOI: https://doi.org/10.1124/mol.107.036285
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