A REGENERATIVE LINK IN THE IONIC FLUXES THROUGH THE WEAVER POTASSIUM CHANNEL UNDERLIES THE PATHOPHYSIOLOGY OF THE MUTATION

The homozygous weaver mouse displays neuronal degeneration in several brain regions. Previous experiments in heterologous expression systems showed that the G protein-gated inward rectifier K+ channel (GIRK2) b earing the weaver pore-region GYG-to-SYG mutation (i) is not activated by G(beta gamma) subunits, but instead shows constitutive activation, and (ii) is no longer a K+-selective channel but conducts Na+ as well . The present experiments on weaverGIRK2 (wv-GIRK2) expressed in Xenop us oocytes show that the level of constitutive activation depends on I ntracellular Na+ concentration. In particular, manipulations that decr ease intracellular Na+ produce a component of Na+-permeable current ac tivated via a G protein pathway. Therefore, constitutive activation ma y not arise because the weaver mutation directly alters the gating tra nsitions of the channel protein. Instead, there may be a regenerative cycle of Na+ influx through the wvGIRK2 channel, leading to additional Na+ activation. We also show that the wvGIRK2 channel is permeable to Ca2+, providing an additional mechanism for the degeneration that cha racterizes the weaver phenotype. We further demonstrate that the GIRK4 channel bearing the analogous weaver mutation has properties similar to those of the wvGIRK2 channel, providing a glimpse of the selective pressures that have maintained the GYG sequence in nearly all known K channels.