A MICROTUBULE ASSOCIATED PROTEIN IN A GPCR WORLD: MAP6D1 AND SEROTONIN SIGNALLING

Serotonin receptors orchestrate neuronal excitability and plasticity through signalling microdomains at the plasma membrane and in specialised compartments, yet the mechanisms that organise these complexes in space and time remain incompletely understood. MAP6d1 is a neuronal, postnatally expressed protein initially identified as a microtubule stabilising protein and containing membrane-targeting domains. It belongs to the MAP6 family, and its paralog MAP6 has been linked to the development and maintenance of serotonergic connectivity. Importantly, MAP6d1 knock-out mice show behavioural alterations including emotional dysregulation, suggesting that MAP6d1-dependent mechanisms may impact monoaminergic pathways.
We test the hypothesis that MAP6d1 modulates serotonergic GPCR signalling by influencing receptor organisation, trafficking, and downstream pathway activation. Our current focus is the 5-HT2B receptor, an understudied serotonin receptor subtype with emerging behavioural relevance: effects of SSRI antidepressants require functional 5-HT2B receptors, and a population-specific stop-codon variant in HTR2B has been associated with severe impulsivity. We identify an interaction between MAP6d1 and 5-HT2B and observe reduced total 5-HT2B protein levels in MAP6d1-deficient conditions. Domain-mapping further indicates that MAP6d1 membrane-targeting palmitoylation sites and its microtubule-binding domain are required for this interaction, raising the hypothesis that membrane localisation and cytoskeletal association cooperate to organise serotonergic signalling. Using MAP6d1 knock-out mice and primary neuronal cultures, we quantify 5-HT2B distribution and canonical signalling outputs after pharmacological manipulation of 5-HT2B receptors.