Voltage-gated calcium channels mediate intracellular calcium
increase in weaver dopaminergic neurons during stimulation of
D2 and GABAB receptors. J Neurophysiol 92: 3368–3374, 2004. First
published July 7, 2004; doi:10.1152/jn.00602.2004. The weaver (wv)
mutation affects the pore-forming region of the inwardly rectifying
potassium channel (GIRK) leading to degeneration of cerebellar
granule and midbrain dopaminergic neurons. The mutated channel
(wvGIRK) loses its potassium selectivity, allowing sodium (Na) and
possibly calcium ions (Ca2) to enter the cell. Here we performed
whole cell patch-clamp recordings combined with microfluorometry
to investigate possible differences in calcium ([Ca2]i) dynamics in
native dopaminergic neurons (expressing the wvGIRK2 subunits) in
the midbrain slice preparation from homozygous weaver (wv/wv) and
control (/) mice. Under resting conditions, [Ca2]i was similar in
wv/wv compared with / neurons. Activation of wvGIRK2 channels
by D2 and GABAB receptors increased [Ca2]i in wv/wv neurons,
whereas activation of wild-type channels decreased [Ca2]i in /
neurons. The calcium rise in wv/wv neurons was abolished by antagonists
of the voltage-gated calcium channels (VGCC); voltage clamp
of the neuron at 60 mV; and hyperpolarization of the neuron to 80
mV or more, in current clamp, and was unaffected by TTX. Therefore
we propose that wvGIRK2 channels in native dopamine neurons are
not permeable to Ca2, and when activated by D2 and GABAB
receptors they mediate membrane depolarization and an indirect Ca2
influx through VGCC rather than via wvGIRK2 channels. Such
calcium influx may be the trigger for calcium-mediated excitotoxicity,
responsible for selective neuronal death in weaver mic