Molecular and cellular correlates in Kv channel clustering: entropy-based regulation of cluster ion channel density

Scaffold protein-mediated ion channel clustering at unique membrane sites is of immense importance for electrical signaling. Yet, as for any ion channel protein, we still do not know how scaffold protein-channel molecular interaction leads to cellular ion channel clustering and how this process is regulated to affect cluster ion channel density. The voltage-activated potassium channel (Kv) is an excellent model protein to address these questions as the mechanism underlying its interaction with the post-synaptic density 95 (PSD-95) scaffold protein is entropy-based and is controlled by the length of the extended ‘ball and chain’ sequences comprising the channel terminal regions. Using super-resolution imaging microscopy to address PSD-95-mediated Kv channel clustering, we examined how Kv channel ‘chain’ length affects cluster Kv channel density. Our study revealed that ‘chain’ length regulates Kv channel membrane density with a ‘bell’-shaped dependence, reflecting balance between thermodynamic considerations controlling ‘chain’ recruitment of PSD-95 and steric hindrance due to spatial proximity of many ion channel molecules. Our results thus reveal an entropy-based regulation mode of cluster channel density that mirrors the entropy-based regulation of the Kv channel-PSD-95 interaction. The implications of these finding for electrical signaling will be discussed.