Obesity‐associated mutant melanocortin‐4 receptors with normal Gαs coupling frequently exhibit other discoverable pharmacological and biochemical defects

Mutations in the melanocortin‐4 receptor (MC4R) are the most common cause of early syndromic obesity known. Most of these mutations result in a loss of protein expression, α‐melanocyte‐stimulating hormone binding, receptor trafficking or coupling to the stimulatory G‐protein, Gαs. However, approximately 26% of the obesity‐associated mutations characterised to date exhibit none of these pharmacological defects. In the present study, we investigated seven of these apparently normal mutant MC4R in more detail and found that the majority (five of the seven) exhibit marked defects including defective binding of another endogenous melanocortin ligand, defective glycosylation, and defective recruitment of β‐arrestin. These data provide support for two hypotheses: (i) that the majority of these rare, obesity‐associated mutations are likely defective and causative of obesity and (ii) that β‐arrestin recruitment is a valuable marker of normal MC4R function. Recent work has demonstrated a statistical correlation between the efficacy of β‐arrestin recruitment to the MC4R and body mass index; however, the data reported here demonstrate both decreased and increased β‐arrestin signalling in obesity‐associated MC4R mutations.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152000/1/jne12795_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152000/2/jne12795-sup-0001-FigS1-S4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152000/3/jne12795.pd

sj-docx-1-hpp-10.1177_15248399221151176 – Supplemental material for Understanding Physical Distancing and Face Mask Use Across High-Risk African American Subgroups During the COVID-19 Pandemic: Application of Health Belief Model

Supplemental material, sj-docx-1-hpp-10.1177_15248399221151176 for Understanding Physical Distancing and Face Mask Use Across High-Risk African American Subgroups During the COVID-19 Pandemic: Application of Health Belief Model by Jamal Moss, Leah Alexander, Iman Barré, Imari Parham, Taneisha Gillyard, Jamaine Davis and Jennifer Cunningham-Erves in Health Promotion Practice</p

G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons

The regulated release of anorexigenic α-MSH and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the CNS plays a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data showα-MSH is an agonist that couples the receptor to the Gαs signaling pathway(1), while AgRP binds competitively to block α-MSH binding(2), and block the constitutive activity mediated by the ligand-mimetic amino terminal domain of the receptor(3). Here, we show that regulation of firing activity of hypothalamic PVN neurons by α-MSH and AgRP can be mediated independently of Gαs signaling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Further, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signaling appears central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signaling, including the gene dosage effect of MC4R(4), and the sustained effects of AgRP on food intake(5)