G protein Signaling, Journeys Beyond the Plasma Membrane

G proteins classically associated with the 7TM or serpentine receptors generally exist as a heterotrimeric complex consisting of alpha, beta and gamma subunits. These proteins serve as transducers of extracellular signal from plasma membrane to cellular interior. Binding of G protein-coupled receptor (GPCR) with a ligand leads to their activation, followed by that of G alpha, which then dissociates from G beta gamma subunits and initiate downstream effects through plasma membrane-localized effectors. This plasma membrane-restricted view of G proteins was challenged when they were found to be present in various intracellular locations such as endomembranes, cytoskeleton, mitochondria, and nucleus thereby opening up newer spatial domains for the action of these signaling molecules. Many recent studies have addressed the spatiotemporal dynamics underlying this atypical distribution and the G proteins have been shown to undergo activation-dependent as well as activation-independent relocalization. This spatially `directed' targeting of G proteins provides them rapid access to intracellular communication network without relying on diffusible second messengers. Here, we present a consolidated review of the existing knowledge about the presence and physiological roles for G proteins in these atypical locations, along with the mechanistic knowhow presently known about underlying processes.