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Pattern of Intra-Family Hetero-Oligomerization Involving the G-Protein-Coupled Secretin Receptor

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Abstract

Oligomerization of G-protein-coupled receptors (GPCRs) is emerging as a mechanism for regulation and functional modification, although it has been studied most extensively for Family A receptors. Family B receptors have clear structural differences from Family A. In this paper, we have systematically evaluated GPCRs that are capable of association with the prototypic Family B secretin receptor. All of the receptor constructs were shown to traffic normally to the plasma membrane. We utilized receptor bioluminescence resonance energy transfer (BRET) to determine the presence of constitutive and ligand-dependent receptor association. Extensive intra-family and no cross-family association was observed. Of the nine Family B receptors studied, all constitutively yielded a significant BRET signal with the secretin receptor, except for the calcitonin receptor. Each of the associating hetero-oligomeric receptor pairs generated a BRET signal of similar intensity, less than that of homo-oligomeric secretin receptors. BRET signals from some receptor pairs were reduced by ligand occupation, but none were increased by this treatment. Thus, Family B GPCR oligomerization occurs, with many structurally related members associating with each other. The specific functional implications of this need to be further evaluated.

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Abbreviations

BRET:

bioluminescence resonance energy transfer

CLR:

calcitonin receptor-like receptor

CTR:

calcitonin receptor

FRET:

fluorescence resonance energy transfer

GHRHR:

growth hormone releasing hormone receptor

GLP1R:

type 1 glucagon-like peptide receptor

GLP2R:

type 2 glucagon-like peptide receptor

PTH1R:

type 1 parathyroid hormone receptor

PTH2R:

type 2 parathyroid hormone receptor

Rlu:

Renilla luciferase

SecR:

secretin receptor

VIP:

vasoactive intestinal polypeptide

VPAC1R:

type 1 vasoactive intestinal polypeptide receptor

VPAC2R:

type 2 vasoactive intestinal polypeptide receptor

YFP:

yellow fluorescent protein

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Acknowledgments

The authors thank Ms. L.-A. Bruins for excellent technical assistance and Ms. E. Posthumus for secretarial assistance. This work was supported by grants from the National Institutes of Health, DK46577 (LJM), National Health and Medical Research Council of Australia (NHMRC) grant 436780 (PMS), and by the Fiterman Foundation (LJM). PMS is a NHMRC Principal Research Fellow.

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Authors and Affiliations

  1. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 13400 East Shea Blvd., Scottsdale, AZ, 85259, USA

    Kaleeckal G. Harikumar & Laurence J. Miller

  2. Department of Pharmacology, Monash University, Clayton, Victoria, 3800, Australia

    Maria M. Morfis & Patrick M. Sexton

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  1. Kaleeckal G. Harikumar
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  2. Maria M. Morfis
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  3. Patrick M. Sexton
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  4. Laurence J. Miller
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Correspondence to Laurence J. Miller.

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Harikumar, K.G., Morfis, M.M., Sexton, P.M. et al. Pattern of Intra-Family Hetero-Oligomerization Involving the G-Protein-Coupled Secretin Receptor. J Mol Neurosci 36, 279–285 (2008). https://doi.org/10.1007/s12031-008-9060-z

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  • DOI: https://doi.org/10.1007/s12031-008-9060-z

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