Tuning pacemaker frequency of individual dopaminergic neurons by Kv4.3L and KChip3.1 transcription

The activity of dopaminergic (DA) substantia nigra (SN) neurons is essential for voluntary movement control. An intrinsic pacemaker in DA SN neurons generates their tonic spontaneous activity, which triggers dopamine release. We show here, by combining multiplex and quantitative real-time single-cell RT- PCR with slice patch-clamp electrophysiology, that an A-type potassium channel mediated by Kv4.3 and KChip3 subunits has a key role in pacemaker control. The number of active A-type potassium channels is not only tightly associated with the pacemaker frequency of individual DA SN neurons, but is also highly correlated with their number of Kv4.3L (long splice variant) and KChip3.1 (long splice variant) mRNA molecules. Consequently, the variation of Kv4alpha and Kv4beta subunit transcript numbers is sufficient to explain the full spectrum of spontaneous pacemaker frequencies in identified DA SN neurons. This linear coupling between Kv4alpha as well as Kv4beta mRNA abundance, A-type channel density and pacemaker frequency suggests a surprisingly simple molecular mechanism for how DA SN neurons tune their variable firing rates by transcriptional control of ion channel genes.