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Science Signaling  09 Feb 2010:
Vol. 3, Issue 108, pp. ec45
DOI: 10.1126/scisignal.3108ec45

In the classical model of signaling by G protein–coupled receptors (GPCRs), a single ligand binds to a single GPCR, which transduces a signal by coupling to the appropriate G protein. Many studies have suggested that GPCRs can dimerize or oligomerize; however, this concept is controversial, because some receptors definitively signal in a monomeric state, and most of the evidence of signaling by dimeric GPCRs comes from studies of transfected cells in vitro (see commentary by Vassart). Noting that some glycoprotein hormone receptors appear to act in vitro by trans activation (intermolecular cooperation), Rivero-Müller et al. studied signaling by mutant forms of luteinizing hormone receptor (LHR). One form contained a mutation that prevented the binding of its ligand, LH, whereas the second form lacked two transmembrane domains, rendering it incapable of coupling to G proteins to produce the second messenger cAMP. The authors first showed that both receptor forms physically interacted in transfected HEK 293 cells and that cells that contained both receptors, but not cells expressing one or the other receptor, responded to LH to generate cAMP. The authors then generated transgenic mice, on an LHR-knockout background, that expressed one or other of the mutant LHRs. As expected, these mice were infertile and exhibited hypogonadism, the same phenotype exhibited by LHR-knockout mice. However, when these mice were crossbred, the resulting animals expressed both receptor forms and showed normal sexual development and were as fertile as wild-type mice. Whether these findings can be extended to other classes of GPCR remains to be seen, but together, these data are suggestive of functional cooperation of GPCRs in vivo.

A. Rivero-Müller, Y.-Y. Chou, I. Ji, S. Lajic, A. C. Hanyaloglu, K. Jonas, N. Rahman, T. H. Ji, I. Huhtaniemi, Rescue of defective G protein–coupled receptor function in vivo by intermolecular cooperation. Proc. Natl. Acad. Sci. U.S.A. 107, 2319–2324 (2010). [Abstract] [Full Text]

G. Vassart, An in vivo demonstration of functional G protein–coupled receptor dimers. Proc. Natl. Acad. Sci. U.S.A. 107, 1819–1820 (2010). [Full Text]

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