Dimerization of GPCRs

The earlier computational studies (151,152,175,184,185) considered both domain-swapped and contact dimers as equally possible mechanisms of GPCR oligomerization. In contrast, the later computational studies on GPCR oligomerization (186-189) take into account only the hypothesis of contact dimers, supported by the more recent experimental evidence. For the prediction of heterodimer interfaces, the recent studies use a modified CMA methodology, termed subtractive correlated mutation (SCM) analysis (187,188). A similar method for the identification of physically interacting protein pairs has recently been reported in the literature (180). 

Baneres, J. L., and Parello, J. (2003). Structure-based analysis of GPCR function Evidence for a novel pentameric assembly between the dimeric leukotriene B4 receptor BLT1 and the G-protein./ Mol. Biol. 329, 815-829. 

Agonist occupancy of GPCRs, such as the delta opioid receptor, leads to physiological effects through interactions with heterotrimeric G proteins. Such G proteins consist of a Ga subunit and its Gpy dimeric partner. There are four major families of Ga proteins with different profiles of effector interaction 1) Gas, which activate adenylyl cyclase 2) Gai/o, so-called inhibitory G proteins named for their ability to inhibit adenylyl cyclase, but interact with many effectors 3) Gaq/11, which activate phospholipase C- 3 (PLC- 3) and 4) Gal2/13, which may regulate small GTP-binding proteins. Delta opioid receptors, like mu and kappa opioid receptors, couple to mem-... 

The recent explosion of number of papers on GPCR dimerization is summarized in several reviews.81112 This chapter is devoted to briefly show importance of oligomerization of GPCRs, current state of knowledge in this area and potential applications. 

The issue of dimerization of type C (glutamate receptor class) is clearly set. Type C GPCRs form dimers by covalent linkage of disulfide bond at their extracellular N-terminal domains (e.g. metabotropic glutamate receptor) or by strong non-covalent, intermolecular interactions (e.g. two y-aminobutyric acid, GABA, receptor subtypes). But is dimerization state also required for their function ... 

The classical view of GPCR signal transduction involves activation of trimeric G-proteins, and in the case of chemokine receptors, Gai is key, as indicated by their sensitivity to pertussis toxin. However, evolving theories of dimerization-induced signal transduction add an intermediate... 

One final development worthy of note here is the development of novel anticancer agents that are dimeric bradykinin analogs. There has been a long-term interest in cross-linked kinin analogs as both agonists and antagonists of GPCRs... 

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