Endocrine Abstracts

Together with Profs Lefkowitz and Kobilka, G-protein-coupled receptors (GPCRs) have taken the stage in the 2012 Nobel award for Chemistry. The Royal Swedish Academy of Sciences states that ‘About half of all medications achieve their effect through G-protein-coupled receptors’. As shown in previous talks in this session, GPCRs are not acting individually; often they form homodimers and, more interestingly, they may occur as heterodimers. Heteromers open a completely new scenario for structural and functional diversity and for drug discovery. By consensus in the field a GPCR heteromer is a macromolecular complex, composed of at least two different receptor units with biochemical properties that are demonstrably different from those of the individual components¹. In fact a precise quaternary structure of the whole complex is needed for heteromer-specific signaling and function⁴.

The seminal work by Rivero-Müller et al.⁵ shows that transgenic mice coexpressing binding-deficient and signaling-deficient forms of LH receptor 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. Other examples are constituted by chemokine receptors that regulate neuroendocrine actions (reviewed in Guyon & Nahon³) and by pineal gland adrenergic and dopamine receptors whose circadian-related heteromerization modulate melatonin synthesis and release².

On the one hand, the talk will provide examples of heteromer alteration in disease and the notion that current GPCR-based therapies are in fact targeting receptor heteromers. On the other hand, a variety of current strategies to design and screen heteromer-selective drugs will be presented. Advantages of heteromer-selective drugs are a more directed targeting, for instance pre- vs post-synaptic in the nervous system, and less side effects.

References

1. Ferré S, et al. Building a new conceptual framework for receptor heteromers. Nat Chem Biol 2009 5 (3) 131–134.

2. González S, et al. Circadian-related heteromerization of adrenergic and dopamine D4 receptors modulates melatonin synthesis and release in the pineal gland. PLoS Biol 2012 10 (6) e1001347. (doi: 10.1371/journal.pbio.1001347).

3. Guyon A & Nahon JL. Multiple actions of the chemokine stromal cell-derived factor-1α on neuronal activity. J Mol Endocrinol 2007 38 (3) 365–376. (Review).

4. Navarro G, et al. Interactions between intracellular domains as key determinants of the quaternary structure and function of receptor heteromers. J Biol Chem 2010 285 (35) 27346–27359.

5. Rivero-Müller A, et al. Rescue of defective G protein-coupled receptor function in vivo by intermolecular cooperation. PNAS 2010 107 (5) 2319–2324. (doi: 10.1073/pnas.0906695106).