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 nucleoide 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 signaling 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 nulcleotide exchange factors or guanine nucleotide dissociation inhibitors and may also influence subunit interactions by interaction with G beta gamma. 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.