Cav1.3 Channel Voltage Dependence, Not Ca2+ Selectivity, Drives Pacemaker Activity and Amplifies Bursts in Nigral Dopamine Neurons

Cav1.3 (α1D) L-type Ca2+ channels have been implicated in substantia nigra (SN) dopamine (DA) neuron pacemaking and vulnerability to Parkinson's disease. These effects may arise from the depolarizing current and cytoplasmic Ca2+ elevation produced by Cav1.3 channels at subthreshold membrane potentials. However, the assumption that the Ca2+ selectivity of Cav1.3 channels is essential has not been tested. In this study the properties of SN DA neuron L-type Ca2+ channels responsible for driving pacemaker activity in juvenile rat brain slices were probed by replacing native channels blocked with the dihydropyridine nimodipine with virtual channels generated by dynamic clamp. Surprisingly, virtual L-type channels that mimic native and recombinant Cav1.3 channels supported pacemaker activity even though dynamic clamp currents are not carried by Ca2+. This effect is specific because pacemaker activity could not be restored by tonic current injection, virtual nonselective leak channels or virtual NMDA receptors, which share with L-type channels a negative slope conductance region in their current–voltage (I–V) curve. Altering virtual channels showed that the production of pacemaker activity depended on the characteristic voltage dependence of DA neuron L-type channels, while activation kinetics and reversal potential were not critical parameters. Virtual L-type channels also supported slow oscillatory potentials and enhanced firing rate during evoked bursts. Thus, Cav1.3 channel voltage dependence, rather than Ca2+ selectivity, drives pacemaker activity and amplifies bursts in SN DA neurons.