Förster resonance energy transfer (FRET) biosensors have provided much evidence for compartmentalised signalling following activation of G protein-coupled receptors (GPCRs). This localised signalling occurs within distinct plasma membrane microdomains and at sub cellular locations including endosomes, mitochondria, Golgi and the nucleus. Notable advances linking compartmentalisation to physiology have been made in two major areas: linking compartmentalised cAMP production by the β2-adrenoceptor to excitation-contraction coupling in the heart; and selectively antagonising GPCRs within early endosomes to provide more efficacious inhibition of pain transmission. Important technological advances are also highlighted, including various approaches for the local activation of receptors, and the rational design of a FRET biosensor with a functional affinity that is not affected by the addition of a targeting sequence.
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