Functional Analysis of the weaver Mutant GIRK2 K+ Channel and Rescue of weaver Granule Cells

In the neurological mutant mouse weaver, granule cell precursors proliferate normally in the external germinal layer of the cerebellar cortex, but fail to differentiate. Granule neurons purified from weaver cerebella have greatly reduced G protein-activated inwardly rectifying K+ currents; instead, they display a constitutive Na+ conductance. Expression of the weaver GIRK2 channel in oocytes confirms that the mutation leads to constitutive activation, loss of monovalent cation selectivity, and increased sensitivity to three channel blockers. Pharmacological blockade of the Na+ influx in weaver granule cells restores their ability to differentiate normally. Thus, Na+ flux through the weaver GIRK2 channel underlies the failure of granule cell development in situ.