Regulator of G protein signaling proteins: Novel multifunctional drug targets

G protein-coupled receptors (GPCRs) play a major role in signal transductio n and are targets of many therapeutic drugs. The regulator of G protein sig naling (RGS) proteins form a recently identified protein family, and they s trongly modulate the activity of G proteins. Their best known function is t o inhibit G protein signaling by accelerating GTP hydrolysis [GTPase activa ting protein (GAP)] thus turning off G protein signals. RGS proteins also p ossess non-GAP functions, through both their RGS domains and various non-RG S domains and motifs (e.g., GGL, DEP, DH/PH, PDZ domains and a cysteine str ing motif). They are a highly diverse protein family, have unique tissue di stributions, are strongly regulated by signal transduction events, and will likely play diverse functional roles in living cells. Thus they represent intriguing, novel pharmacological/therapeutic targets. Drugs targeting RGS proteins can be divided into five groups: 1) potentiators of endogenous ago nist function, 2) potentiators/desensitization blockers of exogenous GPCR a gonists, 3) specificity enhancers of exogenous agonists, 4) antagonists of effector signaling by an RGS protein, and 5) RGS agonists, In addition, a n ovel subsite distinction within the RGS domain has been proposed with signi ficant functional implications and defined herein as "A-site" and "B-site". Therefore, RGS proteins should provide exciting new opportunities for drug development.