Forefronts in Nephrology402

Control of subcellular localization and function of inwardlyrectifying K channels by PDZ-anchoring proteins

YOSHIHISA KURACHI

Department of Pharmacology II, Graduate School of Medicine, Osaka University, Osaka, Japan

Kir3.2c are ESKV. The channels were localized specifi-The control of subcellular localization is an essentialcally at the postsynaptic membrane on the dendrites ofmechanism for ion channels to play specific functionaldopaminergic neurons. Kir3.2c, but not Kir3.2a, couldroles in various polarized cells, such as neurons and epi-bind a PDZ domain-containing protein, PSD-95. Thethelial cells. We found that anchoring proteins that con-heterologously expressed KG channels composed oftain PDZ domains such as PSD-95/SAP90 and SAP97Kir3.2a and Kir3.2c or Kir3.2a alone were activated byplay critical roles in the control of subcellular localizationG-protein stimulation, but expression of Kir3.2c aloneand function of some of inwardly rectifying K (Kir) chan-was not. However, the anchoring proteins confer thenels.G-protein sensitivity to the homomeric Kir3.2c channelKir4.1/KAB-2, cloned by our group, was shown to bethrough their GK domain [7].predominantly expressed in glial cells in the brain and

Therefore, not only subcellular localization, but alsoretina [1–4]. We found that (1) Kir4.1 is distributed inthe pore function of some Kir channels are criticallya clustered manner on the retinal Mueller cell mem-controlled by PDZ domain-containing anchoring pro-brane; (2) the clustering distribution is probably con-teins in vivo.trolled by the interaction between Kir4.1 and SAP97, a

PSD anchoring protein; (3) the C-terminal amino acids,REFERENCESSNV, in Kir4.1 may be critical for the protein-protein1. Takumi T, Ishii T, Horio Y, et al: A novel ATP-dependent inwardinteraction; (4) laminin and insulin signals are essential

rectifier potassium channel expressed predominantly in glial cells.for maintaining the clustered distribution of Kir4.1, J Biol Chem 270:16339–16346, 1995which involves tyrosine kinase activity; (5) aquaporin 4 2. Horio Y, Hibino H, Inanobe A, et al: Clustering and enhanced

activity of an inwardly rectifying potassium channel, Kir4.1, by an(AQP4), whose amino acids at the C-terminal end areanchoring protein, PSD-95/SAP 90 family. J Biol Chem 272:12885–LSSV, is co-localized with Kir4.1 on retinal Mueller cells, 12888, 1997

which seems to be controlled by associated proteins 3. Ishii M, Horio Y, Tada Y, et al: Expression and clustered distribu-tion of an inwardly rectifying potassium channel, KAB-2/Kir4.1, onother than SAP97; and (6) SAP97 enhances the channelmammalian retinal Muller cell membrane: their regulation by insulin

activity of Kir4.1 in a heterologous expression system. and laminin signals. J Neurosci 17:7725–7735, 19974. Nagelhus EA, Horio Y, Inanobe A, et al: Subcellular coexpressionG protein-gated K (KG) channels generate slow inhibi-

of the inwardly rectifying K� channel Kir4.1 and water aquaporin-4tory postsynaptic potentials in the brain [5]. Currentin retinal Muller cells suggests coupling between K� siphoning and

opinion suggests that neuronal KG channels are hetero- water transport. Glia 26:47–54, 19995. Yamada M, Inanobe A, Kurachi Y: G protein regulation of potas-tetramers of Kir3.1 and Kir3.2. Kir3.2 has at least four

sium ion channels. Pharmacol Rev 50:723–757, 1998splicing variants named Kir3.2a-Kir3.2d. We found that 6. Inanobe A, Yoshimoto Y, Horio Y, et al: Characterization of Gthe KG channels in substantia nigra (SN) are an assembly protein-gated K� channels composed of Kir3.2 subunits in substantia

nigra. J Neuroscience 19:1006–1017, 1999of Kir3.2a and Kir3.2c [6]. Kir3.2c is 11 amino acids7. Hibino H, Inanobe A, Tanemoto M, et al: Anchoring proteinslonger than Kir3.2a, which is the only divergent part confer G protein sensitivity to an inwardly rectifying K� channel

between the two clones. The C-terminal amino acids of through the GK domain. EMBO J 19:78–83, 2000