# Agonist-selective activation of individual G-proteins by muscarinic receptors

## TL;DR

This paper shows how new compounds can selectively activate specific G-proteins through muscarinic receptors, offering potential for targeted therapies.

## Contribution

Novel tetrahydropyridine-based agonists show distinct G-protein coupling profiles compared to carbachol.

## Key findings

- Tetrahydropyridine-based agonists exhibit unique signaling profiles when coupling with G-protein α subunits.
- Coupling with Gα varies among muscarinic receptor subtypes, suggesting potential for subtype selectivity.
- These agonists may aid in understanding pathway-specific activation and developing selective muscarinic drugs.

## Abstract

Selective activation of individual subtypes of muscarinic receptors is a promising way to safely alleviate a wide range of pathological conditions in the central nervous system and the periphery as well. The flexible G-protein interface of muscarinic receptors allows them to interact with several G-proteins with various efficacy, potency, and kinetics. Agonists biased to the particular G-protein mediated pathway may result in selectivity among muscarinic subtypes and, due to the non-uniform expression of individual G-protein alpha subunits, possibly achieve tissue specificity. Here, we demonstrate that novel tetrahydropyridine-based agonists exert specific signalling profiles in coupling with individual G-protein α subunits. These signalling profiles profoundly differ from the reference agonist carbachol. Moreover, coupling with individual Gα induced by these novel agonists varies among subtypes of muscarinic receptors which may lead to subtype selectivity. Thus, the novel tetrahydropyridine-based agonist can contribute to the elucidation of the mechanism of pathway-specific activation of muscarinic receptors and serve as a starting point for the development of desired selective muscarinic agonists.