**3.1 Dimerization interface**

Growing experimental data support the view that 7TMRs exist and function as contact dimers or higher order oligomers with TM regions at the interfaces. In contact dimers/oligomers of 7TMRs, the original TM helical-bundle topology of each individual protomer is preserved and interaction interfaces are formed by lipid-exposed surfaces. Although domain-swap models, i.e. models in which domains TM1/TM5 and TM6/TM7 would exchange between protomers, have also been proposed in the literature, there is there is limited direct evidence that supports these assumptions. On the other hand, compelling experimental evidence exists for the involvement of lipid exposed surfaces of TM1, TM4 and/or TM5 at the dimerization/oligomerization interfaces of several 7TMRs. Besides, the interface may depend on additional stabilizing factors such as the coiled-coil interactions reported in the GABAB receptor and the disulfide bridge interactions in the muscarinic and the other class C receptors (reviewed by (Filizola)). A web service, named G-protein coupled Receptors Interaction Partners (GRIP) that predicts the interfaces for 7TMRs oligomerization is also available at http://grip.cbrc.jp/GRIP/index.html (Nemoto et al., 2009). G protein coupled Receptor Interaction Partners DataBase (GRIPDB) has also been developed, which provides information about 7TMRs oligomerization i.e. experimentalaly indentified 7TMRs oligomers, as well as suggested interfaces for the oligomerization (Nemoto et al., 2011).

#### **3.2 Therapeutic application and drug discovery**

7TMRs are one of the most important drug targets in the pharmaceutical industry; approximately 40% of the prescription drugs on the market target 7TMRs, but only 5% of the known 7TMR targets are utilized. Agonists and antagonists of 7TMRs are used in the treatment of diseases of every major organ system including the central nervous system, cardiovascular, respiratory, metabolic and urogenital systems. The most exploited 7TMR drug targets include AT1 angiotensin, adrenergic, dopamine and serotonin (5 hydroxytryptamine, 5-HT) receptor subtypes (Schoneberg et al., 2004). For instance, antagonists of AT1 angiotensin II receptors are used to prevent diabetes mellitus-induced renal damage and to treat essential hypertension and congestive heart failure. β-adrenergic receptor antagonists, acting on β1- and/or β2-adrenergic receptors, are used in patients with congestive heart failure and to treat hypertension and coronary heart disease, while β2 adrenergic receptor agonists are used in the treatment of asthma, chronic obstructive pulmonary disease and to delay preterm labor. Dopamine receptor antagonists, primarily acting on D2 receptors, are utilized in the treatment of schizophrenia, while dopamine receptor agonists (e.g. precursor for dopamine levodopa (L-dopa)) remain the standard for treating Parkinson's disease. Inhibitors of 5-HT uptake, which act as indirect agonists at various subtypes of 5-HT receptors, are used to treat major depressive disorders (Schoneberg et al., 2004).

The increasing importance of dimerization for 7TMRs naturally suggests its possible relevance to drug discovery. It seems that the inclination to hetero-dimerize is common among the 7TM members and that the tissue-specific expression patterns probably underlay the creation of relevant receptor pairs. However, 7TMRs expression has been shown to be altered in some pathological situations. In support to the latter preeclampsia was the first disorder linked to alteration in the AT1−bradykinin B2 receptor hetero-dimerization (AbdAlla et al., 2001). Opioid and dopamine receptor hetero-dimerization has also been comprehensively studied, since their putative ligands are used in pathological conditions such as basal ganglia disorders, schizophrenia, drug addiction and pain. The increase in the dopamine D1-D3 hetero-dimer was shown to be involved in L-dopa-induced dyskinesia in patients with Parkinson's disease and the addition of an adenosine A2A receptor antagonist potentiates the anti-parkinsonian effect of L-dopa. Hetero-dimers of glutamate receptors mGluR2 and 5-HT2A have been specifically associated with hallucinogenic responses in schizophrenia. Furthermore, the opioid δ-μ receptor hetero-dimer is a better target than either μ or δ receptors alone, since blockade of the δ receptor decreases tolerance to the analgesic effects of the most used μ receptor agonist, morphine (reviewed by (Ferré & Franco, 2010; Kenakin & Miller, 2010)). These observations would probably led to broaden the therapeutic potential of drug targeting 7TMRs and it is also anticipated that the evolving concepts of 7TMR dimerization will be implemented in the BRET-based drug discovery and development process (reviewed by (Casado et al, 2009)).
