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.
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