A fast and tiny current as common generator of slow regular pacemaking in brain and heart

Fyon, A.; Pavlova, O.; Schaar, N.; Mesirca, P.; Brandoit, J.; RInglet, S.; Franci, A.; Mangoni, M. E.; Roeper, J.; Drion, G.; Seutin, V.; Jehasse, K.

doi:10.1101/2025.10.30.685563

bioRxiv · 10.1101/2025.10.30.685563

A fast and tiny current as common generator of slow regular pacemaking in brain and heart

Fyon, A.·Pavlova, O.·Schaar, N.·Mesirca, P.·Brandoit, J.·RInglet, S.·Franci, A.·Mangoni, M. E.·Roeper, J.·Drion, G.·Seutin, V.·Jehasse, K.

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Abstract

Slow pacemaking is a key physiological process in specific excitable cells, yet its underlying mechanism remains debated. Here we identify a conserved, voltage-dependent pacemaker current that is essential for slow, regular firing in both midbrain dopaminergic neurons and sinoatrial node myocytes. Conductance-based models incorporating this current reproduce stable pacemaking, requiring a fast-activating, small-amplitude current. This is further confirmed by dynamic-clamp experiments in dopaminergic neurons. Replacing the pacemaker current in a model with a voltage-independent conductance such as the non-selective sodium leak channels fails to sustain slow rhythmicity, highlighting the necessity for an adequate voltage dependence. Our results suggest a novel and shared biophysical mechanism for slow pacemaking in neuronal and cardiac systems.

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Fyon, A., Pavlova, O., Schaar, N., Mesirca, P., Brandoit, J., RInglet, S., Franci, A., Mangoni, M. E., Roeper, J., Drion, G., Seutin, V., Jehasse, K.. 2025-10-31. A fast and tiny current as common generator of slow regular pacemaking in brain and heart. https://doi.org/10.1101/2025.10.30.685563

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