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 base-pair mutation in the Girk2 gene, which encodes a G-protein-activated inwardly rectifying potassium channel, GIRK2. The mutation results in a Gly to Ser substitution at residue 156, in the putative pore-forming region of the potassium channel. In the present study, we used Xenopus 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 channel properties such as activation by the mu opioid receptor. The resulting increase in basal Na+ permeability causes a marked depolarization of oocytes expressing the mutant GIRK2 protein. This result was observed even when the mutant GIRK2 was coexpressed with GIRK1, a situation more analogous to that seen in vivo. Thus, the increased Na+ permeability and resulting depolarization may contribute to the pathology of cerebellar granule cells and substantia nigra dopaminergic neurons observed in the weaver mice.
Tong
Y
Y
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202, USA.
Wei
J
J
Zhang
S
S
Strong
J A
JA
Dlouhy
S R
SR
Hodes
M E
ME
Ghetti
B
B
Yu
L
L
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D003001:Cloning, Molecular; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008818:Mice, Neurologic Mutants; D008845:Microinjections; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger / Q000008:administration & dosage / Q000378:metabolism; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology; D014982:Xenopus laevis
D000700:Analgesics; D004745:Enkephalins; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011957:Receptors, Opioid; D011994:Recombinant Proteins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D012964:Sodium; D011188:Potassium