A C-terminal PDZ binding domain modulates the function and localization of Kv1.3 channels

Abstract

The voltage-gated potassium channel, Kv1.3, plays an important role in regulating membrane excitability in diverse cell types ranging from T-lymphocytes to neurons. In the present study, we test the hypothesis that the C-terminal PDZ binding domain modulates the function and localization of Kv1.3. We created a mutant form of Kv1.3 that lacked the last three amino acids of the C-terminal PDZ-binding domain (Kv1.3ΔTDV). This form of Kv1.3 did not bind the PDZ domain containing protein, PSD95. We transfected wild type and mutant Kv1.3 into HEK293 cells and determined if the mutation affected current, Golgi localization, and surface expression of the channel. We found that cells transfected with Kv1.3ΔTDV had greater current and lower Golgi localization than those transfected with Kv1.3. Truncation of the C-terminal PDZ domain did not affect surface expression of Kv1.3. These findings suggest that PDZ-dependent interactions affect both Kv1.3 localization and function. The finding that current and Golgi localization changed without a corresponding change in surface expression suggests that PDZ interactions affect localization and function via independent mechanisms.

Caveolin interaction governs Kv1.3 lipid raft targeting

“…It is tempting to speculate that different structural tertiary configurations of bulky domains could condition protein–protein interactions with MAGUK proteins, such as PSD95 or SAP97, that interact differently with Kv channels 37 38 39 . This could be explained by supramolecular complexes formed by Kv1.5, Cav1 and SAP97, which further supports our Kv1.5 and PSD95 data in HEK Cav1 cells 33 52 53 .…”

Decrease of a Current Mediated by K v 1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism

“…Theoretically, the reduction of the K v 1.3 current could relate to a decreased expression of the K v 1.3 channels and/or to alterations of their trafficking and regulatory mechanisms. Currents carried by K v 1.3 channels are regulated by serine/threonine (Kupper et al, 1995) and tyrosine phosphorylation (Fadool et al, 1997), co-expression of KCNE4 (Grunnet et al, 2003) and b subunits (McCormack et al, 1999), ubiquitination (Henke et al, 2004), and interactions with scaffolding proteins (Doczi et al, 2011). Preliminary findings show that SCINs display K v 1.3 subunit immunoreactivity in 6-OHDA mice (Figure S6).…”

The C-terminus SH3-binding domain of Kv1.3 is required for the actin-mediated immobilization of the channel via cortactin

“…The binding of cortactin and PDZ proteins to Kv channels occurs at the C-terminal region of the channel, with cortactin binding associated with a 19–amino acid sequence in Kv1.2 channels and PDZ binding occurring at a TDV amino acid motif in Kv1.3 and Kv1.4 channels ( Imamura et al. , 2002 ; Marks and Fadool, 2007 ; Doczi et al. , 2011 ).…”