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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.

2025-10-31 physiology
10.1101/2025.10.30.685563 bioRxiv
Show 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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