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A glutamate residue at the C terminus regulates activity of inward rectifier K+ channels: implication for Andersen's syndrome.
Chen, Lei; Kawano, Takeharu; Bajic, Sibinka; Kaziro, Yoshito; Itoh, Hiroshi; Art, Jonathan J; Nakajima, Yasuko; Nakajima, Shigehiro.
Afiliação
  • Chen L; Department of Anatomy and Cell Biology, University of Illinois, Chicago, IL 60612, USA.
Proc Natl Acad Sci U S A ; 99(12): 8430-5, 2002 Jun 11.
Article em En | MEDLINE | ID: mdl-12034888
ABSTRACT
G protein-coupled inward rectifiers (GIRKs) are activated directly by G protein betagamma subunits, whereas classical inward rectifiers (IRKs) are constitutively active. We found that a glutamate residue of GIRK2 (E315), located on a hydrophobic domain of the C terminus, is crucial for the channel activation. This glutamate (or aspartate) residue is conserved in all members of the Kir family. Substitution of alanine for the glutamate on GIRK1, GIRK2, and IRK2, expressed in HEK293 cells, greatly reduced the whole-cell currents. The whole-cell current of GIRK channels with a constitutively active gate, GIRK2(V188A), [Yi, B. A., Lin, Y. F., Jan, Y. N. & Jan, L. Y. (2001) Neuron 29, 657-667] was also reduced by the same glutamate mutation. Mean open time and conductance of single channels in GIRK2 and IRK2 were not affected by the mutation, indicating that the reduced whole-cell current resulted from a lowered probability of channel activation. The mutated GIRK and IRK showed normal trafficking to the cell membrane. The mutated GIRK2 retained the ability to interact with G protein betagamma subunits, and it showed almost the same inwardly rectifying property as the wild type. The mutated GIRK1 and GIRK2 retained ion selectivity to K(+) ions. This glutamate residue corresponds to one of the residues causing Andersen's syndrome [Plaster, N. M., Tawil, R., Tristani-Firouzi, M., Canun, S., Bendahhou, S., Tsunoda, A., Donaldson, M. R., Iannaccone, S. T., Brunt, E., Barohn, R., et al. (2001) Cell 105, 511-519]. Our interpretation is that this region of the glutamate residue is crucial in relaying the activating message from the ligand sensor region to the gate.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Paralisias Periódicas Familiares / Síndrome do QT Longo / Ativação do Canal Iônico / Ácido Glutâmico / Substituição de Aminoácidos / Canais de Potássio Corretores do Fluxo de Internalização Limite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2002 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Paralisias Periódicas Familiares / Síndrome do QT Longo / Ativação do Canal Iônico / Ácido Glutâmico / Substituição de Aminoácidos / Canais de Potássio Corretores do Fluxo de Internalização Limite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2002 Tipo de documento: Article País de afiliação: Estados Unidos