Impermeability of the GIRK2 weaver channel to divalent cations

Asingle amino acid mutation (G156S) in the putative pore-forming regionof the G protein-sensitive, inwardly rectifying K⁺ channelsubunit, GIRK2, renders the conductance constitutively active andnonselective for monovalent cations. The mutant channel subunit(GIRK2wv) causes the pleiotropic weaver disease inmice, which is characterized by the selective vulnerability ofcerebellar granule cells and Purkinje cells, as well as dopaminergicneurons in the mesencephalon, to cell death. It has beenproposed that divalent cation permeability through constitutivelyactive GIRK2wv channels contributes to a rise in internalcalcium in the GIRK2wv-expressing neurons, eventually leadingto cell death. We carried out comparative studies of recombinantGIRK2wv channels expressed in Xenopus oocytes and COS-7cells to determine the magnitude and relative permeability of theGIRK2wv conductance to Ca²⁺. Data from thesestudies demonstrate that the properties of the expressed current differin the two systems and that when recombinant GIRK2wv isexpressed in mammalian cells it is impermeable to Ca²⁺.