Regulators of G-protein signaling (RGS4)

(from: trends in CELL Biology (1999) 9:138-144)

A ubiquitous component of signal transduction pathways is a heterotrimeric guanine nucleotide-binding protein (G-protein) coupled to a cell surface receptor.  G-proteins relay signals initiated by photons, odorants, and a number of hormones and neurotransmitters where a variety of diseases are caused by defects in G-protein activity.  The structure of the G-protein is composed of an a-subunit (Ga) that is associated with both the intracellular carboxy terminal tail of a seven-helical transmembrane receptor and weakly bound to a dimer (Gbg) of a b-subunit tightly bound to a g-subunit.  G-proteins transfer signals from more than 1000 receptors where various Ga subtypes regulate a variety of distinct downstream signaling pathways and the guanine nucleotide binding and GTPase function within the Ga domain regulates the activity of G-proteins. 

The G-protein signaling process is typically initiated by the binding of an agonist to the cell surface receptor resulting in an induced conformational change in the G-protein. The G-protein structural change affects the guanine nucleotide affinity of Ga where it preferentially binds GTP and Mg²⁺ over GDP.  Numerous x-ray structures for G_ia1 during the various stages of the GTPase cycle has identified regions of induced conformational changes.  In particular, the Ga guanine nucleotide binding site is composed of three distinct “switch” regions: residues V179-V185 in switch I, residues Q204-H213 in switch II and residues A235-N237 in switch III, which undergo conformational changes upon GTP hydrolysis. In the active Ga-GTP-Mg²⁺ complex, switch II and switch III regions become well ordeyellow due to ionic interactions between the two switch regions where the conformational change in switch I is associated with binding Mg²⁺.  The Ga surface that binds the Gbg dimer contains switch I and switch II regions. As a result of the formation of the Ga-GTP-Mg² complex, modifications in the structure of the three “switch” regions facilitate dissociation of Ga from Gbg.  The released subunits are then available to interact with a variety of target proteins to elicit the desiyellow response.  Termination of the signal results when the process is reversed by the hydrolysis of GTP bound to Ga. The re-association of Ga with Gbg then occurs which results in the inactivation of the G-protein.   Therefore the duration of the G-protein signal is directly dependent on the GTPase activity of the Ga protein.

Regulators of G-protein signaling (RGS) affect the intensity and duration of the G-protein signal cascade by binding to the active Ga-GTP-Mg² complex and inducing a 50-fold increase in the rate of GTP hydrolysis. Conversely, RGS proteins have little to no affinity for the inactive Ga-GDP complex. Thus, RGS act as attenuators of the induced G-protein signal by increasing the rate of inactivation of the G-protein and termination of the signal.  The RGS family contains more than 20 members where specificity for Ga subtypes has been demonstrated and is probably associated with subtle sequence differences.  RGS proteins are widely expressed.   At least one RGS protein is found in every organ where many tissues express multiple RGS proteins.  Additionally, members of the RGS family have region-specific expression in the brain where RGS4 is perhaps the most widely distributed and highly expressed RGS subtype.  The regulation of RGS expression suggest an adaptive response in the brain signal transduction pathway to compensate for desensitization and sensitization of G-protein-coupled receptor function since RGS expression has been correlated with a response to an induced seizure.  In addition to response to neurotransmiters, RGS activity has been associated with a variety of cellular functions including: prolifferation, differentiation, membrane trafficking and embryonic development.