Postsynaptic density-93 clusters Kv1 channels at axon initial segments independently of Caspr2.
Postsynaptic density-93 (PSD-93)/Chapsyn-110 is a PDZ (PSD-95/Discs large/zona occludens-1) domain-containing membrane-associated guanylate kinase (MAGUK) that functions as a scaffold to assemble channels, receptors, and other signaling proteins at cell membranes. PSD-93 is highly enriched at synapses, but mice lacking this protein have no synaptic structural abnormalities, probably because of overlapping expression and redundancy with other MAGUKs. Consequently, the function of PSD-93 is not well understood. Here, we show that PSD-93, but not other MAGUKs, is enriched at the axon initial segment (AIS), where it colocalizes with Kv1.1, Kv1.2, Kv1.4, and Kvbeta2 subunit-containing K(+) channels, Caspr2, and TAG-1 (transient axonal glycoprotein-1). When coexpressed with Kv1 channels in heterologous cells, PSD-93 induces formation of large cell-surface clusters. Knockdown of PSD-93 in cultured hippocampal neurons by RNA interference disrupted Kv1 channel localization at the AIS. Similarly, PSD-93-/- mice failed to cluster Kv1 channels at the AIS of cortical and hippocampal neurons. In contrast, Caspr2, which mediates Kv1 channel clustering at the juxtaparanode, is not required for localization of Kv1 channels at the AIS. These results show PSD-93 mediates AIS accumulation of Kv1 channels independently of Caspr2.
Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Yasuhiro
Y
Ogawa
Ido
I
Horresh
James S
JS
Trimmer
David S
DS
Bredt
Elior
E
Peles
Matthew N
MN
Rasband
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D015816:Cell Adhesion Molecules, Neuronal / Q000172:deficiency / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D058969:Contactin 2; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051637:Shaker Superfamily of Potassium Channels / Q000378:metabolism*; D018709:Statistics, Nonparametric; D014162:Transfection / Q000379:methods
D015816:Cell Adhesion Molecules, Neuronal; C548675:Cntn2 protein, mouse; C548676:Cntn2 protein, rat; C491322:Cntnap1 protein, mouse; D058969:Contactin 2; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C489787:MAP2 protein, rat; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C501451:Mpp2 protein, rat; D021122:Protein Subunits; D051637:Shaker Superfamily of Potassium Channels; D049452:Green Fluorescent Proteins; D051528:Guanylate Kinases