Acetylcholine is a neuromodulator that critically regulates cognition by activating muscarinic M1 receptors. Interestingly M1 receptors are located throughout neurons (including at the axon initial segment (AIS)). Activation of these have a variety of location-dependent effects on neuronal activity. We have explored the intracellular mechanisms underpinning these diverse location-dependent effects. We find that stimulation of M1 receptors at the AIS triggers beta-arrestin 2 and not G-proteins to induce a persistent reduction in the action potential threshold and enhanced neuronal firing. This intrinsic plasticity was dependent on agonist-induced phosphorylation of M1 receptors by casein kinase 2. Beta-arrestin 2 recruitment by M1 receptors initiated a unique downstream signalling pathway. In contrast, soma-dendrite M1 receptor activation instigated G-protein signalling to reversibly modify membrane properties. Our findings reveal that M1 receptors situated in distinct compartments diversely transform hippocampal neuron activity by triggering unique signalling modalities – a process we term location-dependent system bias.
Celebrating Physiology in London (University College London, UK) (2026) Proc Physiol Soc 73, SA03
Research Symposium: Location-dependent cholinergic biased signalling regulates axonal intrinsic plasticity in hippocampal neurons
Haojie Sun1, Rafael Lujan2, Xuewei Yu1, Ryan Dowsell3, Timothy Church1, Katharine Gibson4, Andrew Tobin4, Matthew Gold1, Mala Shah1
1University College London UK, 2Universidad Castilla La Mancha Spain, 3University College London UK, 4University of Glasgow UK
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Where applicable, experiments conform with Society ethical requirements.