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The Journal of Neuroscience, January 1, 2000, 20(1):156-162

Neuronal Inwardly Rectifying K⁺ Channels Differentially Couple to PDZ Proteins of the PSD-95/SAP90 Family

Ralf B. Nehring¹, Erhard Wischmeyer¹, Frank Döring¹, Rüdiger W. Veh², Morgan Sheng³, and Andreas Karschin¹

¹ Molecular Neurobiology of Signal Transduction, Max-Planck-Institut for Biophysical Chemistry, 37070 Göttingen, Germany, ² Department of Anatomy, Charité, 10098 Berlin, Germany, and ³ Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts 02114

Several signaling proteins clustered at the postsynaptic density specialization in neurons harbor a conserved C-terminal PDZ domain recognition sequence (X-S/T-X-V/I) that mediates binding to members of the PSD-95/SAP90 protein family. This motif is also present in the C termini of some inwardly rectifying K⁺ (Kir) channels. Constitutively active Kir2 channels as well as G protein-gated Kir3 channels, which are fundamental for neuronal excitability, were analyzed as candidates for binding to PSD-95/SAP90 family members. Therefore C termini of Kir2.1(+), Kir2.3(+), Kir2.4(), Kir3.1(), Kir3.2(+), Kir3.3(+) and Kir3.4() subunits (+, motif present; , motif absent) were used as baits in the yeast two-hybrid assay to screen for in vivo interaction with PDZ domains 1-3 of PSD-95/SAP90. In contrast to Kir2.1 and Kir2.3, all Kir3 fragments failed to bind PSD-95 in this assay, which was supported by the lack of coimmunoprecipitation and colocalization of the entire proteins in mammalian cells. A detailed analysis of interaction domains demonstrated that the C-terminal motif in Kir3 channels is insufficient for binding PDZ domains. Kir2.1 and Kir2.3 subunits on the other hand coprecipitate with PSD-95. When coexpressed in a bicistronic internal ribosome entry site expression vector in HEK-293 cells macroscopic and elementary current analysis revealed that PSD-95 suppressed the activity of Kir2.3 channels by >50%. This inhibitory action of PSD-95, which predominantly affects the single-channel conductance, is likely attributable to a molecular association with additional internal interaction sites in the Kir2.3 protein.

Key words: inwardly rectifying; Kir channel; GIRK; postsynaptic density; chapsyns; MAGUK; yeast two-hybrid

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Copyright © 2000 Society for Neuroscience  0270-6474/0/201156-07$05.00/0

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