Effect of a partial loss of function <i>MC3R</i> mutation on MC3R+GHSR-1A heterodimer activity and RNF11 regulation

Purpose The melanocortin 3 receptor (MC3R) is a G-protein coupled receptor that has been identified as a regulator of energy balance mechanisms. In addition to its role in weight gain and appetite regulation mechanisms, recent studies have shown that MC3R is important for growth, puberty, circadian rhythms, and liver autophagy. In human populations, loss-of-function mutations of MC3R, particularly the Thr6Lys/Val81Ile MC3R variant are linked to early-onset obesity. This variant is characterized by decreased activity and reduced cAMP signaling capacity. Also, research has indicated that wild type (WT) MC3R and growth hormone secretagogue receptor 1A (GHSR-1A) receptors dimerize and increase MC3R-induced CAMP signaling. Moreover, MC3R can interact with ring finger protein 11 (RNF11), an E3 ligase.
Methods In this study RNF11 was used to examine heterodimerization efficiency and functional properties of both WT and Thr6Lys/Val81Ile MC3R+GHSR-1A by using F & ouml;rster Resonance Energy Transfer (FRET) technique and H187 EPAC CAMP detection biosensor.
Results It was found that overexpression of RNF11 increased the WT MC3R's heterodimerization efficiency and heterodi-mer specific MC3R CAMP production function, whereas no such effect was observed for Thr6Lys/Val81Ile MC3R Conclusion Altered heterodimer function may help explain the signaling insufficiency of the Thr6Lys/Val81Ile MC3R haplotype.