# Structure-guided design of a peripherally restricted chemogenetic system

**URL:** <https://forum.painresearcher.net/t/structure-guided-design-of-a-peripherally-restricted-chemogenetic-system/1328>\
**Category:** Journal Club\
**Created:** [February 5, 2025, 9:49am UTC](https://forum.painresearcher.net/t/structure-guided-design-of-a-peripherally-restricted-chemogenetic-system/1328 "2025-02-05T09:49:23Z")\
**Posts on this page:** 4\
**Page:** 1

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**Author:** ![vhms0706](https://avatars.discourse-cdn.com/v4/letter/v/4bbf92/32.png) [@vhms0706](https://forum.painresearcher.net/u/vhms0706)\
**Post date:** [February 5, 2025, 9:49am UTC](https://forum.painresearcher.net/t/structure-guided-design-of-a-peripherally-restricted-chemogenetic-system/1328/1 "2025-02-05T09:49:23Z")

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Recent paper from Dr. Bryan Roth Lab on developing peripherally restricting DREADD system using receptor engineering: [Structure-guided design of a peripherally restricted chemogenetic system - ScienceDirect](https://www.sciencedirect.com/science/article/pii/S0092867424012753?via%3Dihub)

I have a really naive quesiton. Does this mean that we can leverage the same system for any GPCRs of which its expression is peripherally restricted to create another potential DREADD chemogenetic actuators?

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**Author:** ![achamess](https://yyz2.discourse-cdn.com/flex030/user_avatar/forum.painresearcher.net/achamess/32/534_2.png) [@achamess](https://forum.painresearcher.net/u/achamess)\
**Post date:** [February 22, 2025, 12:15pm UTC](https://forum.painresearcher.net/t/structure-guided-design-of-a-peripherally-restricted-chemogenetic-system/1328/2 "2025-02-22T12:15:31Z")

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Not a naive question. Perhaps? But you would need to engineer a ligand to bind the GPCR of interest. @MGeron can probably illuminate for us.

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**Author:** ![MGeron](https://avatars.discourse-cdn.com/v4/letter/m/df788c/32.png) [@MGeron](https://forum.painresearcher.net/u/MGeron)\
**Post date:** [February 24, 2025, 3:43am UTC](https://forum.painresearcher.net/t/structure-guided-design-of-a-peripherally-restricted-chemogenetic-system/1328/3 "2025-02-24T03:43:30Z")

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GPCRs that are exclusively expressed in the periphery would be a promising starting point, as they inherently provide an extra layer of selectivity for peripheral activity. You would still need to modify that GPCR so that it becomes unresponsive to its endogenous ligand and develop a new, peripherally restricted ligand that activates only the mutated receptor and not the wild-type receptor (or other GPCRs).

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**Author:** ![achamess](https://yyz2.discourse-cdn.com/flex030/user_avatar/forum.painresearcher.net/achamess/32/534_2.png) [@achamess](https://forum.painresearcher.net/u/achamess)\
**Post date:** [February 24, 2025, 12:15pm UTC](https://forum.painresearcher.net/t/structure-guided-design-of-a-peripherally-restricted-chemogenetic-system/1328/4 "2025-02-24T12:15:14Z")

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Thanks @MGeron. Excellent points. Lots of work to arrive at that point. Nice work on the paper btw! Very enabling tool for the pain reserch community.