title: Cav1.3 channel voltage dependence, not Ca2+ selectivity, drives pacemaker activity and amplifies bursts in nigral dopamine neurons.
abstract: Ca(v)1.3 (alpha 1D) L-type Ca(2+) 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 Ca(2+) elevation produced by Ca(v)1.3 channels at subthreshold membrane potentials. However, the assumption that the Ca(2+) selectivity of Ca(v)1.3 channels is essential has not been tested. In this study the properties of SN DA neuron L-type Ca(2+) 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 Ca(v)1.3 channels supported pacemaker activity even though dynamic clamp currents are not carried by Ca(2+). 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, Ca(v)1.3 channel voltage dependence, rather than Ca(2+) selectivity, drives pacemaker activity and amplifies bursts in SN DA neurons.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Ilva
authors.initials: I
authors.lastname: Putzier
authors.forename: Paul H M
authors.initials: PH
authors.lastname: Kullmann
authors.forename: John P
authors.initials: JP
authors.lastname: Horn
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Levitan
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009553:Nimodipine / Q000494:pharmacology; D010507:Periodicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; C093712:Cacna1d protein, rat; D009553:Nimodipine; D002118:Calcium; D004298:Dopamine