Multiple PIP₂ binding sites in Kir2.1 inwardly rectifying potassium channels

Abstract

Inwardly rectifying potassium channels require binding of phosphatidylinositol-4,5-bisphosphate (PIP 2 ) for channel activity. Three independent sites (aa 175^206, aa 207^246, aa 324^365) were located in the C-terminal domain of Kir2.1 channels by assaying the binding of overlapping fragments to PIP 2 containing liposomes. Mutations in the first site, which abolished channel activity, reduced PIP 2 binding of this fragment but not of the complete C-terminus. Point mutations in the third site also reduced both, channel activity and PIP 2 binding of this segment. The relevance of the third PIP 2 binding site provides a basis for the understanding of constitutively active Kir2 channels. ß

A novel neuropsychiatric phenotype of KCNJ2 mutation in one Taiwanese family with Andersen–Tawil syndrome

“…T192I, which was located in the putative cytoplasmic chain after the second transmembrane region M2 of Kir2.1, is postulated to have a crucial role in arranging the location of the phosphatidylinositol-4, 5-bisphosphate (PIP2) binding motif (PKKR, 186-189). 9 This codon has been reported to have one confirmed mutation, p.Thr192Ala, in two independent Japanese patients with ATS. 5,9 Therefore, given its amino acid position and co-segregation with disease clinical phenotype, we postulate that T192I is most likely the cause of disease in our index patient.…”

“…9 This codon has been reported to have one confirmed mutation, p.Thr192Ala, in two independent Japanese patients with ATS. 5,9 Therefore, given its amino acid position and co-segregation with disease clinical phenotype, we postulate that T192I is most likely the cause of disease in our index patient.…”

Mutations in Nature Conferred a High Affinity Phosphatidylinositol 4,5-Bisphosphate-binding Site in Vertebrate Inwardly Rectifying Potassium Channels

“…1A). Thus, AqKir is the only known functional Kir channel that lacks multiple residues previously shown to be important for regulation by PIP 2 (27,36). A BLAST search for additional distant relatives of the vertebrate Kir channels found three putative Kir channels in the genome of the sea anemone Nematostella vectensis (Nv).…”

Direct Modulation of Kir Channel Gating by Membrane Phosphatidylinositol 4,5-Bisphosphate

“…However, the nature of the phosphoinositide-channel interaction remains elusive. For one extensively studied group, the inward rectifier K (Kir) channels, there is an emerging consensus that a direct interaction occurs between cytoplasmic domains of the channel and inositol headgroups, based on electrophysiological analysis (5, 13-16) and biochemical analysis of isolated channel domains (5,17,18). Direct interaction of functional channels with phospholipids in the membrane has been difficult to demonstrate unequivocally, and without this, quantification of the dose-response relationships for channel modulation by phospholipids is obviated, and further mechanistic understanding is limited (19, 20).…”