Key result
SCRIB and PSD93 enable AIS Kv1 channel clustering via SCRIB linkage to AnkyrinG.
Why the study?
Clustering mechanisms of the large protein complex containing AIS Kv1 potassium channels remain unknown.
Identifies SCRIB and PSD93 as essential scaffolding proteins for clustering Kv1 potassium channels at the axon initial segment.
Extends AIS scaffolding map in rodents; leaves open whether SCRIB/PSD93 targeting alters excitability in disease models.
Action potentials are initiated and modulated at the axon initial segment (AIS) by highly clustered ion channels. Voltage-gated Kv1 potassium channels underlie most outward AIS K + current. AIS Kv1 channels exist in a large protein complex including ADAM22, Caspr2, and LGI1. However, their clustering mechanisms remain unknown. Because Kv1 channels have a highly conserved PDZ-binding motif, we used CRISPR-based genome editing to screen 18 PDZ domain-containing proteins identified in our previous AIS proximity proteome for their AIS localization. Among these, we found that the scaffolding proteins SCRIB and PSD93 are highly enriched at the AIS. Using CRISPR-mediated knockout, cell surface clustering assays, and coimmunoprecipitation, we show that SCRIB and PSD93 bind to and are required for AIS Kv1 channel clustering, whereas SCRIB links the AIS Kv1 channel protein complex to the master AIS scaffolding protein AnkyrinG. These results define a hierarchy of scaffolding proteins that combine to cluster AIS Kv1 channels.
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Zhang et al. (2025) studied this question. CRISPR-mediated knockout of SCRIB and PSD93 vs. Control gRNAs was evaluated on Kv1 channel clustering at the axon initial segment. SCRIB and PSD93 bind to and are required for AIS Kv1 channel clustering, with SCRIB linking the AIS Kv1 channel protein complex to the master AIS scaffolding protein AnkyrinG.
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