Concerning family A GPCRs although

Concerning family A GPCRs, although it has been described that several receptors are able to operate as monomers (Arcemisbéhère et al., 2010; Bayburt et al., 2011; Chabre & le Maire, 2005; Ernst, Gramse, Kolbe, Hofmann, & Heck, 2007; Hanson et al., 2007; Kuszak et al., 2009; Whorton et al., 2007), experimental data have shown that these receptors may be expressed as a mixture of monomers and homodimers/oligomers (Nemoto, Yamanishi, Limviphuvadh, Saito, & Toh, 2016; Teichmann et al., 2014; Vischer, Castro, & Pin, 2015), and that oligomerization is required for receptor maturation, surface delivery and function (Angers et al., 2000; Angers, Salahpour, & Bouvier, 2002; Fotiadis et al., 2003; Gahbauer & Böckmann, 2016; Han, Moreira, Urizar, Weinstein, & Javitch, 2009; Herrick-Davis, Weaver, Grinde, & Mazurkiewicz, 2006; Hurevich, Talhami, Shalev, & Gilon, 2014; Jin et al., 2018; Lao et al., 2017; Liste et al., 2015; Lopez-Gimenez, Canals, Pediani, & Milligan, 2007; Ng et al., 2013; Wade et al., 2011). The existing controversy about the functionality of monomers or the dimerization requirement may come from the differences in the nature of the receptor, the experimental conditions of the assays or in the nature of the different detection technologies (Lao et al., 2017). As an example of oligomerization of class A GPCRs, using dual-color photoactivation localization microscopy with photoactivatable dyes, Jonas, Fanelli, Huhtaniemi, and Hanyaloglu (2015) reported that the luteinizing hormone receptor is organized in a mixture of monomers, dimers and higher order oligomers (<5 receptors) at the MPEP Hydrochloride membrane with distinct spatial geometries. Likewise, M1 muscarinic, dopamine D2, β1-adrenergic and chemokine receptors (CXCR4) can exist in a dynamic equilibrium between monomers/dimers/oligomers, that can be regulated by selective agonists, antagonists or bivalent ligands (Calebiro et al., 2013; Pediani, Ward, Godin, Marsango, & Milligan, 2016; Tabor et al., 2016). Albizu et al. (2010) demonstrated the in vivo existence of native oxytocin receptor dimers and Herrick-Davis, Grinde, Lindsley, Cowan, and Mazurkiewicz (2012); Herrick-Davis, Grinde, Cowan, and Mazurkiewicz (2013); Herrick-Davis et al. (2015) provided strong experimental evidence that adrenergic, muscarinic, dopamine, and serotonin 5-HT2C receptors form homodimers endogenously expressed in their native cellular environment. Cai, Bai, Zhang, Wang, and Chen (2017) revealed monomer-to-dimer interconversion of the apelin receptor on the cell membrane, with dimers acquiring novel functional characteristics, such as distinct G-protein binding profile and cellular responses after agonist stimulation. Very recently, Parmar, Grinde, Mazurkiewicz, and Herrick-Davis (2017), using bioluminescence resonance energy transfer (BRET), bimolecular fluorescence complementation (BiFC) and fluorescence correlation spectroscopy, indicated that β2-adenergic receptors are predominantly homodimers. Likewise, Jastrzebska et al. (2017) demonstrated that the human red cone opsin forms stable dimers in the live cell membranes, being required for dimerization the aminoacids I230, A233 and M236. Other class A GPCRs that have been also found to form homomers, specially in the last decade, are adenosine A1, A2A and A3, dopamine D1 and D3, serotonin 5HT1A, 5HT2A, and 5HT7, adrenergic α1B, cannabinoid CB1, angiotensin AT1, muscarinic M2 and M3, δ, κ and μ opioid, melatonin MT2, and niacin receptors (Ayoub, Levoye, Delagrange, & Jockers, 2004; Bagher, Laprairie, Toguri, Kelly, & Denovan-Wright, 2017; Bonaventura et al., 2015; Cvejic & Devi, 1997; Goin & Nathanson, 2006; Gracia et al., 2013, Gracia et al., 2011; Guitart et al., 2014; He, Fong, von Zastrow, & Whistler, 2002; Herrick-Davis et al., 2013; Jordan & Devi, 1999; Łukasiewicz et al., 2007; Mandrika, Petrovska, & Klovins, 2010; May, Bridge, Stoddart, Briddon, & Hill, 2011; Pou, Mannoury la Cour, Stoddart, Millan, & Milligan, 2012; Szalai et al., 2012; Teitler, Toohey, Knight, Klein, & Smith, 2010).