Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways.

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor expressed at hypothalamic neurons that has an important role in appetite suppression and food intake. Mutations in MC4R are the most common cause of monogenic obesity and can affect multiple signaling pathways including Gs-cAMP, Gq, ERK1/2, β-arrestin recruitment, internalization and cell surface expression. The melanocortin-2 receptor accessory protein 2 (MRAP2), is a single-pass transmembrane protein that interacts with and regulates signaling by MC4R.

Early employment after childbirth: a cross-sectional analysis using data from a national maternity survey in England.

Background: Participation in paid work after childbirth may have important health and socioeconomic impacts on women and their families. We investigated women's employment patterns at six months postpartum and the factors that influence them.

Methods: Using data from a 2018 population-based national maternity survey in England, employment status at six months postpartum was assessed.

An activating CaSR variant with biased signaling reveals a critical residue for Gα11 coupling.

Autosomal dominant hypocalcemia (ADH) is due to enhanced calcium-dependent signaling caused by heterozygous gain-of-function (GOF) variants in the CASR gene (ADH1) or in the GNA11 gene, encoding Gα11 (ADH2). Both ADH1 and ADH2 are associated with hypocalcemia and normal or inappropriately low levels of circulating PTH. ADH1 patients typically manifest hypercalciuria, while ADH2 is associated with short stature in approximately 42% of cases.

The MRAP2 accessory protein directly interacts with melanocortin-3 receptor to enhance signaling.

The central melanocortin system links nutrition to energy expenditure, with melanocortin-4 receptor (MC4R) controlling appetite and food intake, and MC3R regulating timing of sexual maturation, rate of linear growth and lean mass accumulation. Melanocortin-2 receptor accessory protein-2 (MRAP2) is a single transmembrane protein that interacts with MC4R to potentiate it's signalling, and human mutations in MRAP2 cause obesity. Previous studies have been unable to consistently show whether MRAP2 affects MC3R activity.