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PNAS 107 (5): 2319-2324

Copyright © 2010 by the National Academy of Sciences.

From the Cover


Rescue of defective G protein–coupled receptor function in vivo by intermolecular cooperation

Adolfo Rivero-Müllera, Yen-Yin Choub,c, Inhae Jid, Svetlana Lajicb, Aylin C. Hanyaloglub, Kim Jonasb, Nafis Rahmana, Tae H. Jid, and Ilpo Huhtaniemia,b,1

aDepartment of Physiology, University of Turku, 20520 Turku, Finland; bDepartment of Reproductive Biology, Hammersmith Campus, Imperial College London, London W12 0NN, United Kingdom; cInstitute of Clinical Medicine, National Cheng Kung University Medical College and Hospital, Tainan, 701 Taiwan; and dDepartment of Chemistry, University of Kentucky, Lexington, KY 40506-0055

Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved October 26, 2009 (received for review June 18, 2009)

Abstract: G protein–coupled receptors (GPCRs) are ubiquitous mediators of signaling of hormones, neurotransmitters, and sensing. The old dogma is that a one ligand/one receptor complex constitutes the functional unit of GPCR signaling. However, there is mounting evidence that some GPCRs form dimers or oligomers during their biosynthesis, activation, inactivation, and/or internalization. This evidence has been obtained exclusively from cell culture experiments, and proof for the physiological significance of GPCR di/oligomerization in vivo is still missing. Using the mouse luteinizing hormone receptor (LHR) as a model GPCR, we demonstrate that transgenic mice coexpressing binding-deficient and signaling-deficient forms of LHR can reestablish normal LH actions through intermolecular functional complementation of the mutant receptors in the absence of functional wild-type receptors. These results provide compelling in vivo evidence for the physiological relevance of intermolecular cooperation in GPCR signaling.

Key Words: di/oligomerization • luteinizing hormone receptor • testis • transgenic mice • fertility

Freely available online through the PNAS open access option.

Author contributions: A.R.-M., S.L., T.H.J., and I.H. designed research; A.R.-M., Y.-Y.C., I.J., S.L., A.C.H., and K.J. performed research; A.R.-M., Y.-Y.C., I.J., A.C.H., N.R., T.H.J., and I.H. analyzed data; and A.R.-M., Y.-Y.C., S.L., A.C.H., T.H.J., and I.H. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

See Commentary on page 1819.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: ilpo.huhtaniemi{at}

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