Voltage-gated calcium channels mediate intracellular calcium increase in weaver dopaminergic neurons during stimulation of D2 and GABAB receptors.

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 mice