Impermeability of the GIRK2 weaver channel to divalent cations

A single amino acid mutation (G156S) in the putative pore-forming region of the G protein-sensitive, inwardly rectifying K+ channel subunit, GIRK2, re nders the conductance constitutively active and nonselective for monovalent cations. The mutant channel subunit (GIRK2wv) causes the pleiotropic weave r disease in mice, which is characterized by the selective vulnerability of cerebellar granule cells and Purkinje cells, as well as dopaminergic neuro ns in the mesencephalon, to cell death. It has been proposed that divalent cation permeability through constitutively active GIRK2wv channels contribu tes to a rise in internal calcium in the GIRK2wv-expressing neurons, eventu ally leading to cell death. We carried out comparative studies of recombina nt GIRK2wv channels expressed in Xenopus oocytes and COS-7 cells to determi ne the magnitude and relative permeability of the GIRK2wv conductance to Ca 2+. Data from these studies demonstrate that the properties of the expresse d current differ in the two systems and that when recombinant GIRK2wv is ex pressed in mammalian cells it is impermeable to Ca2+.