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 several GPCRs can also continue to activate G proteins from endosomes upon internalisation. Importantly, this signalling from endomembranes mediates alternative cellular responses than signalling at the plasma membrane. Endosomal G protein signalling and their physiological relevance have been abundantly documented for Gα s - and Gα i -coupled receptors. Recently, a few Gα q -coupled receptors have been reported to activate Gα q from endosomes mediating important cellular processes. However, several questions relative to the series of cellular events required to translate Gα q activation from endosomes into cellular responses remain unanswered and constitute a new conundrum. How are these responses mediated in quasi absence of the substrate of the canonical Gα q -activated effector in endosomes? 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 expose and discuss these important questions and proposes possible routes of investigation.