title: Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons.
abstract: Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency-current (f-I) relationship, whereas BK channel inhibition had little effect on the f-I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f-I relationship. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell.
  
  
  CONCLUSIONS
  This work shows that BK calcium-activated potassium channels and Kv2 voltage-activated potassium channels both regulate action potentials in dopamine neurons of the substantia nigra pars compacta. Although both channel types participate in action potential repolarization about equally, they have contrasting and partially opposite effects in regulating neuronal firing at frequencies typical of bursting. Our analysis shows that this results from their different kinetic properties, with fast-activating BK channels serving to short-circuit activation of Kv2 channels, which tend to slow firing by producing a deep afterhyperpolarization. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Tilia
authors.initials: T
authors.lastname: Kimm
authors.affiliation: Cellular Neurophysiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Zayd M
authors.initials: ZM
authors.lastname: Khaliq
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and bruce_bean@hms.harvard.edu.
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Bean
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D005071:Evoked Potentials / Q000187:drug effects; D005260:Female; D007700:Kinetics; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011999:Recruitment, Neurophysiological; D051669:Shab Potassium Channels / Q000187:drug effects / Q000502:physiology*; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D051669:Shab Potassium Channels
keywords: action potential clamp; bursting; guangxitoxin-1E; paxilline