Abstract
The activation of G-protein-coupled receptors (GPCRs) is traditionally
measured either by monitoring downstream physiological events or
by membrane-based biochemical assays. Neither of these approaches
permits detailed kinetic or spatial analysis of receptor activation
and signaling. Recently, several optical techniques have been developed
to monitor receptor activation either by using purified reconstituted
GPCRs or by observing GPCRs, G proteins and second messengers in
intact cells. These techniques are providing, literally, new views
on both the mechanistic basis of the signaling process and the kinetic
and spatial properties of GPCR-mediated signals. They suggest that
agonists can activate GPCRs within milliseconds, that different compounds
can induce distinct active conformations of GPCRs, that G-protein
activation is the rate-limiting step in GPCR signaling, and that
cellular signals can be temporally and spatially confined. They are
also raising controversial issues, such as whether or not receptors
and G proteins are pre-coupled and whether G proteins dissociate
during activation.
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