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Vol. 297, Issue 3, 837-845, June 2001
Departments of Pharmacology (H.Z., R.R.N.) and Internal
Medicine/Hypertension (R.R.N.), The University of Michigan, Ann Arbor,
Michigan
G protein-coupled receptors (GPCRs) play a major role in signal
transduction and are targets of many therapeutic drugs. The regulator
of G protein signaling (RGS) proteins form a recently identified
protein family, and they strongly modulate the activity of G proteins.
Their best known function is to inhibit G protein signaling by
accelerating GTP hydrolysis [GTPase activating protein (GAP)] thus
turning off G protein signals. RGS proteins also possess non-GAP
functions, through both their RGS domains and various non-RGS domains
and motifs (e.g., GGL, DEP, DH/PH, PDZ domains and a cysteine string
motif). They are a highly diverse protein family, have unique tissue
distributions, 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 agonist function, 2)
potentiators/desensitization blockers of exogenous GPCR agonists, 3)
specificity enhancers of exogenous agonists, 4) antagonists of effector
signaling by an RGS protein, and 5) RGS agonists. In addition, a novel
subsite distinction within the RGS domain has been proposed with
significant functional implications and defined herein as "A-site"
and "B-site". Therefore, RGS proteins should provide exciting new
opportunities for drug development.
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