Gα_q signalling from endosomes: a new conundrum

G-protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors, and are involved in the transmission of a variety of extracellular stimuli such as hormones, neurotransmitters, light and odorants into intracellular responses. They regulate every aspect of physiology and, for this reason, about one third of all marketed drugs target these receptors. Classically, upon binding to their agonist, GPCRs are thought to activate G-proteins from the plasma membrane and to stop signalling by subsequent desensitisation and endocytosis. However, accumulating evidence indicates that, upon internalisation, some GPCRs can continue to activate G-proteins in endosomes. Importantly, this signalling from endomembranes mediates alternative cellular responses other than signalling at the plasma membrane. Endosomal G-protein signalling and its physiological relevance have been abundantly documented for Gα_s- and Gα_i-coupled receptors. Recently, some Gα_q-coupled receptors have been reported to activate Gα_q on endosomes and mediate important cellular processes. However, several questions relative to the series of cellular events required to translate endosomal Gα_q activation into cellular responses remain unanswered and constitute a new conundrum. How are these responses in endosomes mediated in the quasi absence of the substrate for the canonical Gα_q-activated effector? Is there another effector? Is there another substrate? If so, how does this alternative endosomal effector or substrate produce a downstream signal? This review aims to unravel and discuss these important questions, and proposes possible routes of investigation.