Activation of heterotrimeric G-proteins independent of a G-protein coupled receptor and the implications for signal processing.

Heterotrimeric G-proteins are key transducers for signal transfer from outside the cell, mediating signals emanating from cell-surface G-protein coupled receptors (GPCR). Many, if not all, subtypes of heterotrimeric G-proteins are also regulated by accessory proteins that influence guanine nucleotide binding, guanosine triphosphate (GTP) hydrolysis, or subunit interactions. One subgroup of such accessory proteins (activators of G-protein signaling; AGS proteins) refer to a functionally defined group of proteins that activate selected G-protein signaring systems in the absence of classical G-protein coupled receptors. AGS and related proteins provide unexpected insights into the regulation of the G-protein activation-deactivation cycle. Different AGS proteins function as guanine nucleotide exchange factors or guanine nucleotide dissociation inhibitors and may also influence subunit interactions by interaction with GBgamma. These proteins play important roles in the generation or positioning of signaling complexes and of the regulation of GPCR signaling, and as alternative binding partners for G-protein subunits. Perhaps of even broader impact is the discovery that AGS proteins provide a foundation for the concept that heterotrimeric G-protein subunits are processing signals within the cell involving intrinsic cues that do not involve the classical signal input from a cell surface GPCR.