How MC4R variants scramble receptor trafficking
Obesity-linked MC4R mutations disrupt plasma-membrane localization, endocytosis and β-arrestin pathways beyond classical cAMP loss-of-function.
Source
Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation
What they did
Authors assayed dozens of rare and common human MC4R variants for surface expression, endocytosis/trafficking, dimerization, β-arrestin engagement and ERK/cAMP signaling in cells.
What they found
MC4R homodimerizes and undergoes β-arrestin-2–driven endocytosis. Many variants impair trafficking even when cAMP looks normal; gain-of-function alleles link to obesity protection.
The limits
What it doesn't show
Cellular LoF classification is not a full clinical trial; mouse models are still needed for genotype–phenotype dissection.
Key terms
- MC4R
- Melanocortin-4 receptor GPCR controlling energy balance in the brain.
- Endocytosis
- Internalization of surface receptors into endosomes.
- β-arrestin
- Adaptor driving GPCR endocytosis and some non-G-protein signaling.
- Plasma membrane expression
- Amount of receptor present at the cell surface.
- Loss-of-function (LoF)
- Variant that reduces receptor functional output in cells.
Flashcards
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Quiz yourself
MC4R mutations can impair:
Common questions
Can trafficking fail with normal cAMP?
Yes—many variants impair localization/β-arrestin without classic cAMP LoF.
Which arrestin mainly drives MC4R endocytosis?
β-arrestin-2.
What do gain-of-function variants do?
Associate with protection from obesity.
How many rare obesity-linked variants were characterized?
48 rare MC4R variants.
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