8.A.51 The Dipeptidyl-aminopeptidase-like Protein 6 beta subunit of Kv4 channels (DPP6) Family

Auxiliary beta-subunits dictate the physiological properties of voltage-gated K⁺ (K_V) channels in excitable tissues. The dipeptidyl-aminopeptidase-like protein 6 (DPP6) is a specific β-subunit of neuronal K_V4 channels, which may promote gating through interactions between the single transmembrane segment of DPP6 and the channel's voltage sensing domain (VSD) (Maffie and Rudy 2008). A combination of gating current measurements and protein biochemistry (in-vitro translation and co- immunoprecipitations) revealed preferential physical interaction between the isolated K_V4.2-VSD and DPP6 (Dougherty et al. 2009). Significantly weaker interactions were detected between DPP6 and K_V1.3 channels or the K_V4.2 pore domain (McNicholas et al. 2009). More efficient gating charge movement resulting from a direct interaction between DPP6 and the K_V4.2-VSD is unique among the known actions of K_V channel beta-subunits. Thus. the modular VSD of a K_V channel can be directly regulated by transmembrane protein-protein interactions involving an extrinsic β-subunit. Understanding these interactions may shed light on the pathophysiology of recently identified human disorders associated with mutations affecting the dpp6 gene. Loss of DPP6 influences neuronal excitability and promotes neurodegnerative dementia (Cacace et al. 2019).