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This Article Full Text Full Text (PDF) All Versions of this Article: 92/6/3368    most recent 00602.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Guatteo, E. Articles by Mercuri, N. B. Search for Related Content PubMed PubMed Citation Articles by Guatteo, E. Articles by Mercuri, N. B.

Voltage-Gated Calcium Channels Mediate Intracellular Calcium Increase in Weaver Dopaminergic Neurons During Stimulation of D₂ and GABA_B Receptors

¹Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, 00179 Rome; and ²Clinica Neurologica, Università di Tor Vergata, 00133 Rome, Italy

Submitted 14 June 2004; accepted in final form 6 July 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 GABA_B 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 GABA_B 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.