Pharmacological effect of human melanocortin-2 receptor accessory protein 2 variants on hypothalamic melanocortin receptors
Endocrine, 2018•Springer
Abstract Purpose Melanocortin-3 receptor (MC3R), melanocortin-4 receptor (MC4R), and a
recently identified melanocortin-2 receptor accessory protein 2 (MRAP2), are highly
expressed in hypothalamus and coordinately regulate energy homeostasis, but the single
cellular transcriptome of melanocortin system remains unknown. Several infrequent MRAP2
variants are reported from severe obese human patients but the mechanisms on how they
affect melanocortin signaling are unclear. Methods First, we performed in silico analysis of …
recently identified melanocortin-2 receptor accessory protein 2 (MRAP2), are highly
expressed in hypothalamus and coordinately regulate energy homeostasis, but the single
cellular transcriptome of melanocortin system remains unknown. Several infrequent MRAP2
variants are reported from severe obese human patients but the mechanisms on how they
affect melanocortin signaling are unclear. Methods First, we performed in silico analysis of …
Purpose
Melanocortin-3 receptor (MC3R), melanocortin-4 receptor (MC4R), and a recently identified melanocortin-2 receptor accessory protein 2 (MRAP2), are highly expressed in hypothalamus and coordinately regulate energy homeostasis, but the single cellular transcriptome of melanocortin system remains unknown. Several infrequent MRAP2 variants are reported from severe obese human patients but the mechanisms on how they affect melanocortin signaling are unclear.
Methods
First, we performed in silico analysis of mouse hypothalamus RNA sequencing datasets at single-cell resolution from two independent studies. Next, we inspected the three-dimensional conformational alteration of three mutations on MRAP2 protein. Finally, the influence of MRAP2 variants on MC3R and MC4R signaling was analyzed in vitro.
Results
(1) We confirmed the actual co-expression of Mrap2 with Mc3r and Mc4r, and demonstrated more broad distribution of Mrap2-positive neuronal populations than Mc3r or Mc4r in mouse hypothalamus. (2) Compared with wild-type MRAP2, MRAP2N88Y, and MRAP2R125C showed impaired α-MSH-induced MC4R or MC3R stimulation. (3) MRAP2N88Yexhibited enhanced interaction with MC4R protein and its own.
Conclusions
This is the first dedicated description of single-cell transcriptome signature of Mrap2, Mc3r, and Mc4r in the central nerve system and the first evidence describing the unique dimer formation, conformational change, and pharmacological effect of MRAP2 mutations on MC3R signaling.
Springer
