Journal Club 26.06.26

Itch receptor MRGPRX4 interacts with the receptoractivity–modifying proteins

Ilana B. Kotliar1,2,‡ , Emilie Ceraudo1,‡ , Kevin Kemelmakher-Liben1 , Deena A. Oren3 , Emily Lorenzen1 ,
Tea Dodig-Crnkovic4 , Mizuho Horioka-Duplix1 , Thomas Huber1 , Jochen M. Schwenk4 , and
Thomas P. Sakmar1,5,*

Cholestatic itch is a severe and debilitating symptom in liver
diseases with limited treatment options. The class A G proteincoupled
receptor (GPCR) Mas-related GPCR subtype X4
(MRGPRX4) has been identified as a receptor for bile acids,
which are potential cholestatic pruritogens. An increasing
number of GPCRs have been shown to interact with receptor
activity–modifying proteins (RAMPs), which can modulate
different aspects of GPCR biology. Using a combination of
multiplexed immunoassay and proximity ligation assay, we
show that MRGPRX4 interacts with RAMPs. The interaction of
MRGPRX4 with RAMP2, but not RAMP1 or 3, causes attenuation
of basal and agonist-dependent signaling, which correlates
with a decrease of MRGPRX4 cell surface expression as
measured using a quantitative NanoBRET pulse-chase assay.
Finally, we use AlphaFold Multimer to predict the structure of
the MRGPRX4–RAMP2 complex. The discovery that RAMP2
regulates MRGPRX4 may have direct implications for future
drug development for cholestatic itch.