RT Journal Article
SR Electronic
T1 Regulation of G Protein–Coupled Receptor Signaling: Specific Dominant-Negative Effects of Melanocortin 2 Receptor Accessory Protein 2
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra28
OP ra28
DO 10.1126/scisignal.2000593
VO 3
IS 116
A1 Sebag, Julien A.
A1 Hinkle, Patricia M.
YR 2010
UL http://stke.sciencemag.org/content/3/116/ra28.abstract
AB Heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs), which constitute the largest family of membrane proteins, mediate responses to diverse physiological stimuli. The presence of melanocortin 2 receptors (MC2Rs) on the plasma membrane requires the presence of either MC2R accessory protein (MRAP) or MRAP2, which are homologous accessory proteins. Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3′,5′-monophosphate (cAMP). ACTH bound with high affinity to MC2Rs in the presence of MRAP, but not MRAP2. The ability of MRAP and MRAP2 to influence ligand-binding affinity was specific to MC2R, because these proteins had little effect on the binding of NDP-α-melanocyte–stimulating hormone to MC4R or on its stimulation of cAMP responses. These results demonstrate that the balance of stimulatory and inhibitory accessory proteins can control the sensitivity of a GPCR to its natural agonist.