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
Study at a glance
- Design
- Animal / in-vitro — Cell assays of rare and common human MC4R variants for trafficking, dimerization, and signaling
- N
- N=48 · 48 rare obesity-associated MC4R variants plus two common protective alleles (V103I, I251L)
- Population
- Human MC4R variants expressed in cellular assays
- Outcome
- Endocytosis, trafficking, dimerization, and signaling consequences of MC4R variants
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Inspect source passages
How MC4R variants scramble receptor trafficking
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Authors characterized 48 rare MC4R variants.
We characterized 48 rare MC4R variants (minor allele frequency [MAF], <1%) associated with severe obesity in clinically ascertained cohorts (; ; ) and two prevalent MC4R variants (MAF, 1%–2%; V103I and I251L) associated with protection from obesity in large population-derived studies (; ; ; ; A; ).
Up to 25% of MC4R mutations in obese cohorts do not reduce cAMP.
However, up to 25% of MC4R mutations found in obese cohorts do not reduce cAMP production and are therefore classified as wild-type (WT)-like/non-pathogenic ( https://www.mc4r.org.uk ; ).
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.
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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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