Tuning the excitability of midbrain dopamine neurons by modulating the Ca2+ sensitivity of SK channels.
Small conductance Ca(2+) -activated K(+) (SK) channels play a prominent role in modulating the spontaneous activity of dopamine (DA) neurons as well as their response to synaptically-released glutamate. SK channel gating is dependent on Ca(2+) binding to constitutively bound calmodulin, which itself is subject to endogenous and exogenous modulation. In the present study, patch-clamp recording techniques were used to examine the relationship between the apparent Ca(2+) affinity of cloned SK3 channels expressed in cultured human embryonic kidney 293 cells and the excitability of DA neurons in slices from rat substantia nigra using the positive and negative SK channel modulators, 6,7-dichloro-1H-indole-2,3-dione-3-oxime and R-N-(benzimidazol-2-yl)-1,2,3,4-tetrohydro-1-naphtylamine. Increasing the apparent Ca(2+) affinity of SK channels decreased the responsiveness of DA neurons to depolarizing current pulses, enhanced spike frequency adaptation and slowed spontaneous firing, effects attributable to an increase in the amplitude and duration of an apamin-sensitive afterhyperpolarization. In contrast, decreasing the apparent Ca(2+) affinity of SK channels enhanced DA neuronal excitability and changed the firing pattern from a pacemaker to an irregular or bursting discharge. Both the reduction in apparent Ca(2+) affinity and the bursting associated with negative SK channel modulation were gradually surmounted by co-application of the positive SK channel modulator. These results underscore the importance of SK channels in 'tuning' the excitability of DA neurons and demonstrate that gating modulation, in a manner analogous to physiological regulation of SK channels in vivo, represents a means of altering the response of DA neurons to membrane depolarization.
Ji
Huifang
H
Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
Hougaard
Charlotte
C
Herrik
Kjartan Frisch
KF
Strøbaek
Dorte
D
Christophersen
Palle
P
Shepard
Paul D
PD
D015057:1-Naphthylamine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001030:Apamin / Q000008:administration & dosage; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002491:Central Nervous System Agents / Q000008:administration & dosage; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010091:Oximes / Q000008:administration & dosage; D018408:Patch-Clamp Techniques; D010507:Periodicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology
C515166:(R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine; C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D002491:Central Nervous System Agents; D007211:Indoles; C406328:KCNN3 protein, human; D010091:Oximes; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin; D015057:1-Naphthylamine; D002118:Calcium; D004298:Dopamine