THE WEAVER MUTATION CHANGES THE ION SELECTIVITY OF THE AFFECTED INWARDLY RECTIFYING POTASSIUM CHANNEL GIRK2

The weaver mutation in mice has recently been identified as a single b ase-pair mutation in the Girk2 gene, which encodes a G-protein-activat ed inwardly rectifying potassium channel, GIRK2. The mutation results in a Gly to Ser substitution at residue 156, in the putative pore-form ing region of the potassium channel, In the present study, we used Xen opus oocytes to express mutant GIRK2, and to characterize the effects of the mutation on the channel, The mutation results in a loss of the normal high selectivity for K+ over Na+, with little effect on other c hannel properties such as activation by the ma opioid receptor, The re sulting increase in basal Na+ permeability causes a marked depolarizat ion of oocytes expressing the mutant GIRK2 protein, This result was ob served even when the mutant GIRK2 was coexpressed with GIRK1, a situat ion more analogous to that seen in vivo. Thus, the increased Na+ perme ability and resulting depolarization may contribute to the pathology o f cerebellar granule cells and substantia nigra dopaminergic neurons o bserved in the weaver mice.