Rebuttal from Nevin A. Lambert and Jonathan A. Javitch

In their review Bouvier and Hebért (2014) demonstrate how ‘dimer-coloured’ glasses can filter perception, impair recall, and perhaps blind us to alternative hypotheses and contradictory findings. For example, Whorton et al. (2008) demonstrated that rhodopsin monomers reconstituted from detergent into nanodiscs activate transducin as rapidly as native rod membranes, not that reconstituted oligomers activate more quickly than monomers, which was what our colleagues somehow took away. Indeed, forced dimerization of rhodopsin if anything slows transducin activation (Bayburt et al. 2007). Likewise, rows of rhodopsin dimers were cited as structural evidence for oligomerization (Fotiadis et al. 2003), but older observations suggesting that such rows may be related to sample preparation were overlooked (Roof & Heuser, 1982). Large receptor arrays are also very difficult to reconcile with rapid lateral and rotational diffusion of rhodopsin in intact outer segments (Poo & Cone, 1974). Redka et al. (2013) observed some degree of binding cooperativity for most agonists even in detergent, where the receptors they studied were thought to be monomers. Nevertheless, since cooperativity was greater in phospholipid than in detergent it was said to be ‘lost’ when receptors were monomerized. This is a generous interpretation, particularly since detergent also decreased the affinities of both high- and low-affinity sites by 10- to 20-fold. Fonseca & Lambert (2009) was cited as evidence for transient dimers, although this study failed to detect evidence of dimers of any sort. In our view these examples illustrate the degree to which oligomerization has become the default explanation for many observations, and a concept that is more widely accepted than a careful consideration of all available evidence warrants. There is little doubt that class A GPCRs can and do interact in the membrane, but despite initial inferences that these interactions are stable and constitutive, new more discriminating methods suggest that these interactions are transient (Hern et al. 2010; Kasai et al. 2011). Using highly-engineered approaches we and others (Mesnier & Banères, 2004; Vilardaga et al. 2008; Han et al. 2009; Urizar et al. 2011) have shown that receptors in proximity can affect each other, but whether this is relevant in native systems is extraordinarily difficult to establish and simply not yet clear. The potential of heterodimers for improved pharmacotherapies is exciting and has drawn many of us to the field. We certainly agree with our colleagues that ‘much work remains to irrefutably demonstrate [the] functional importance [of dimers] in vivo’, but we must continue to approach this work with unfettered vision, without preconception, and with healthy skepticism.

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Additional information

Competing interests

None declared.

Funding

The authors' research is supported by grants from the National Institute of General Medical Sciences (GM078319), National Institute of Drug Abuse (DA022413), and National Institute of Mental Health (MH54137).