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. 2011 Feb 1:2:2.
doi: 10.3389/fendo.2011.00002. eCollection 2011.

Biological Significance of GPCR Heteromerization in the Neuro-Endocrine System

Maud Kamal  1 , Ralf Jockers
Affiliations

Biological Significance of GPCR Heteromerization in the Neuro-Endocrine System

Maud Kamal et al. Front Endocrinol (Lausanne). .

Abstract

Clustering of proteins in higher order complexes is a common theme in biology and profoundly influences protein function. The idea that seven-transmembrane spanning G protein-coupled receptors (GPCRs) might form dimers or higher order oligomeric complexes has been formulated more than 20 years ago. Since then, this phenomenon has been investigated with many different biochemical and biophysical techniques. The more recent notion of GPCR heteromerization describes the specific association of two different GPCRs. GPCR heteromerization may be of primary importance in neuroendocrinology, as this may explain at least some of the functional crosstalks described between different hormonal systems. Importantly, many GPCR heteromers have distinct functional properties compared to their corresponding homomers. Heteromer-specific pharmacological profiles might be exploited for drug design and open new therapeutic options. GPCR heteromerization has been first studied in heterologous expression systems. Today, increasing evidence for the existence of GPCR heteromers in endogenous systems is emerging providing crucial evidence for the physiological function of GPCR heteromerization.

Keywords: GPCR; direct physical interaction; endocrinology; functional crosstalk; heterodimers.

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Figures

Figure 1
Figure 1
Functional versus physical interaction of GPCRs. (I) In the absence of any physical or functional interaction, the activation of two different GPCRs induces two independent signaling pathways A and B, which consequently result in two independent effects 1 and 2. (II) Physical interaction of two different GPCRs results in the activation of the heteromer-specific signaling pathway C that will be responsible of a downstream effect 3. (III) In the absence of physical interaction, a functional interaction can be observed when signaling pathways A and B crosstalk to produce effect 4.
Figure 2
Figure 2
Detection of homo/heteromer formation by FRET using fluorescent ligands. (I) In the case of homomer formation a FRET signal can be detected between a selective donor (D) ligand I that binds the first protomer and a selective acceptor (A) ligand 1 that binds the second protomer The donor and acceptor ligands can be the same molecule but labeled differently. (II) In the case of heteromer formation, a FRET signal can be detected between a selective donor ligand 1 that binds the first protomer and a selective acceptor ligand 2 that binds the second protomer. In this case, donor and acceptor ligands are different molecules.
Figure 3
Figure 3
G protein-coupled receptors oligomerization by intermolecular functional complementation of mo mutant receptors. (I) Oligomerization of ligand binding deficient receptor mutant (RL−) does not trigger GPCR function. (II) Oligomerization of signaling deficient receptor mutant (Rs−) does not trigger GPCR function. (III) Co-expression of RL− and Rs− restores GPCR function. L; ligand.
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