Endocrine Abstracts

An archetypal view of GPCR signalling depicts cell surface localized receptors activating specific heterotrimeric G-protein signal pathways, which in turn converge on to common downstream pathways. How such signals are translated into the highly diverse cellular and physiological responses that are controlled by this superfamily of receptors has been a long-standing biological question. This question has driven our more current understanding of the complexity of these receptor-signalling systems, yet how such functional pleiotropy in GPCR signalling is decoded to specific downstream cellular responses is unknown. One mechanism that regulates both signal specificity and diversity is membrane trafficking, a system deeply integrated with cell signalling. Our recent studies with the gonadotropin hormone receptors, provides an unprecedented view of how GPCR activity can be regulated at a spatial level. We have demonstrated that specificity in signalling of distinct internalized GPCRs can be achieved by regulated endosomal targeting of receptors upstream of the classic early endosome, a compartment we term the very early endosome (VEE). Importantly, GPCR activation of cAMP-PKA signalling drives its own post-endocytic sorting via a unique VEE recycling mechanism, and spatially restricts endosomal cAMP and MAPK signalling. Spatial encoding of receptor signalling provides a mechanism for reprogramming GPCR activity by altering receptor location across distinct endosomes to create highly regulated and distinct signalling profiles. Such mechanisms may also be altered pathophysiologically and that perturbed gonadotropin-activity in recurrent miscarriage may be due to altered spatial control of GPCR signalling.