A new mech­an­ism that regulates receptors

A new mech­an­ism that regulates receptors

A research team led by Martin Lohse has dis­covered that a pro­tein called RAMP can speed up recept­ors. The mech­an­ism could provide a new tar­get for drugs.

G pro­tein-coupled recept­ors (GPCRs) rep­res­ent the most import­ant drug tar­gets. In the search for such drugs, research interest is now focused on so-called allos­teric mech­an­isms. These are effects medi­ated via sites in the receptor that are dis­tinct from those medi­at­ing the effects of the body’s endo­gen­ous sub­stances, such as hormones.

One such mech­an­ism has now been dis­covered by Martin Lohse’s research team. Using the receptor for para­thyroid hor­mone (PTH - a hor­mone that regulates cal­cium meta­bol­ism and bone form­a­tion) as an example, the team invest­ig­ated the effects of the reg­u­lat­ory pro­tein RAMP. The acronym stands for Receptor Activ­ity Modi­fy­ing Pro­tein. The research­ers showed that RAMP causes pre-activ­a­tion: It makes the recept­ors more recept­ive to their hor­mone, PTH, and they respond faster and stronger.

These obser­va­tions were made pos­sible by novel bio­sensors. They allow the activ­ity of the receptor to be visu­al­ized dir­ectly in the micro­scope. “There is always some­thing new to dis­cover about recept­ors,” com­ments Katar­ina Nemec, first author of the pub­lic­a­tion in the pres­ti­gi­ous journal Pro­ceed­ings of the National Academy of Sci­ences USA (PNAS). “If we can mimic the effects of RAMP with drugs, then we could enhance the effects of PTH in the body. PTH is effect­ive in osteo­porosis, the wide­spread bone weak­ness that occurs primar­ily with age. There is a great need for new and bet­ter drugs here,” adds Pro­fessor Lohse.

Model of a com­plex of PTH-receptor (red), bound PTH (green) and the RAMP2-pro­tein (blue). The image shows, how closely the pro­teins inter­act. Graph­ics: Patrick Scherer

Func­tional mod­u­la­tion of PTH1R activ­a­tion and sig­nal­ing by RAMP2.
Nemec K, Schi­hada H, Kleinau G, Zabel U, Grushevskyi EO, Scheerer P, Lohse MJ, Mai­el­laro I (2022) Proc Natl Acad Sci USA 119:e2122037119.

Fig­ure: The pro­tein RAMP (blue) enhances the action of para­thyroid hor­mone (PTH) on its receptor (red). Both pro­teins are loc­ated in the cell mem­brane (gray). RAMP causes the effects of PTH on the cell to become faster and stronger.
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