Uncovering Isoform-Induced Inhibition in Vesicular Monoamine Transporters

Our recent study, "Splice Isoform Induced Selective Inhibition of Vesicular Monoamine Transporter Assembly Revealed by Multi-level Combinatorial Analysis," investigates the regulation of monoamine loading into synaptic vesicles. This process is a rate-limiting step that directly shapes neurotransmission across dopaminergic, serotonergic, and noradrenergic pathways.

Vesicular Monoamine Transporters determine synaptic tone and have traditionally been modeled as functioning primarily through their full-length canonical isoforms. Alternative splicing generates truncated variants that remain poorly understood within membrane transporter biology. In this research, we mapped how a specific truncated splice isoform of VMAT1 actively interferes with canonical oligomerization.

By integrating structural docking, atomistic lipid bilayer molecular dynamics, and Poisson-Boltzmann Surface-Area binding energy decomposition, we characterized the thermodynamic relationship between the isoform and the canonical protein. We found that the truncated isoform exhibits a higher binding affinity for the canonical VMAT than the canonical protein has for itself. This dynamic shifts the interaction from a contest of overall surface area to one of localized charge intensity.

Because the system energetically favors the heterodimer, the smaller isoform acts as a molecular latch that outcompetes the full-length protein. This establishes the truncated isoform as a direct negative regulator of VMAT assembly. These findings reframe VMAT oligomerization as a splicing-sensitive checkpoint and offer a new mechanistic perspective on synaptic dysfunction in neuropsychiatric and neurodegenerative disorders.

Karagöl, A., & Karagöl, T. (2025). Splice Isoform Induced Selective Inhibition of Vesicular Monoamine Transporter Assembly Revealed by Multi-level Combinatorial Analysis. bioRxiv, 2025-11.

The full study is available here: https://doi.org/10.1101/2025.11.29.691296