Functional crosstalk between GPCRs: with or without oligomerization

Communication between cells requires key and specialized signaling systems, like G-protein-coupled receptors (GPCRs). Cells coexpress a large number of different GPCRs, the activation of which generates multiple signals that are integrated via mechanisms still not well understood. The Class C GPCRs like the metabotropic receptors for glutamate (mGlu), GABA (GABA_B), or calcium ions (CaSR), have been shown to functionally crosstalk with other receptor systems, leading to synergistic or new signaling responses involved in important physiological functions. The Class C GPCRs are well-known dimeric receptors, either homodimeric (mGlu or CaSR) or heterodimeric (GABA_B or taste T1R1/T1R3 and T1R2/T1R3) receptors. Moreover, they have been reported to form oligomeric complexes themselves or associated to other receptors. As the receptor oligomerization often affect binding, activity, or signaling of GPCRs, the formation of receptor heteromers has been used as an explanation for many of the described crosstalk involving these receptors. Here, we will discuss that crosstalk could result not only from receptor oligomerization, but also from colocalized receptor sharing signaling pathways, or from synergistic regulation of signaling crossroads, independently of oligomerization.

Introduction

Powerful receptor systems have been set up during evolution to allow efficient cell–cell communication. One of the crucial receptor systems is the G-protein-coupled receptor (GPCR) family, the dysfunction of which generates a lot of pathologies, making them the focus of intense research for seeking powerful therapeutic strategies (see e.g. [1, 2, 3, 4]). Indeed, GPCRs, formed by seven helix-containing proteins (7TM proteins) coded by the largest mammalian gene family, are already the targets of about 30% of the drugs on the market [5]. Because cells express several GPCR subtypes, GPCR signals are both spatially and time integrated in order to generate appropriate cellular response upon activation of several receptors [6, 7], the disruption of which being potently pathological. But the cellular and molecular mechanisms of GPCR signal integration are still not well understood, like the so-called GPCR crosstalk.

Several possible mechanisms have been proposed, either at the level of the receptors themselves or at the level of their signaling, that could help defining strategies to regulate crosstalk (Figure 1). For example, two decades ago, the discovery that coactivation of GPCRs led to signaling crosstalk opened up to the exploration of complex cellular signaling. For example, the intracellular calcium level can be controlled by two different signaling pathways mobilized by the coactivation of two GPCRs coupled to Gq and Gi/o G proteins, respectively [8, 9, 10]. More recently, the discovery and the study of the role of oligomerization of GPCRs led to the hypothesis that these physical associations rule synergistic and new GPCR signaling responses [11]. The discovery of GPCR oligomerization in different GPCR classes is revolutionizing the analysis of their pharmacology and signaling activity, thus leading to a regain of interest in GPCRs as therapeutic targets and will refresh the seek for drug discovery and therapeutic strategies [12, 13, 14]. A terminology has recently been proposed for receptors composed of several proteins, indicating that only functional entities can be called receptors [15], that is notably valid for the Class C GPCRs.

Indeed, the Class C GPCRs have been the first for which clear evidences showed that a dimeric organization is required for their functioning [16]. Indeed, according to the proposed terminology Class C receptors form either homomeric receptors, like the metabotropic glutamate receptors mGlu1-8 and the calcium receptor CaSR which are composed of two identical subunits, or heteromeric receptors, like the GABA receptor GABA_B made of two different subunits GABA_B1 and GABA_B2, and the taste receptors made of the subunits T1R1 and T1R3 (glutamate umami taste) and T1R2 and T1R3 (sweet taste). These physical dimeric associations have been shown to control, regulate, or modify the receptor synthesis, activity, pharmacology, and signaling. Interestingly, some of these Class C GPCRs could associate even in higher order oligomers of 7TM proteins forming homomers of heteromeric receptors, as demonstrated recently for the GABA_B receptor by Maurel et al. [17^••]. Moreover, Class C GPCRs have been reported to associate with an increasing number of receptor subtypes, thanks to the spreading of powerful new technological tools allowing to study physical protein–protein interaction. Besides, the discovery of functional crosstalk of Class C GPCRs with other receptors, brings a new complexity in the understanding of their physio-pathological roles, which need to be considered when designing new pharmacological tools and concepts, leading to therapeutic strategies [18, 19]. Thus, in order to modulate crosstalk for therapeutic intervention, it is necessary to unravel the molecular mechanisms involved and their relationship with the capability of GPCRs to oligomerize. The present review will focus on a few examples of crosstalk involving Class C GPCRs that will be analyzed in regards of their mechanism and in relation with GPCR oligomerization.