Caveolin interaction governs Kv1.3 lipid raft targeting

Abstract

The spatial localization of ion channels at the cell surface is crucial for their functional role. Many channels localize in lipid raft microdomains, which are enriched in cholesterol and sphingolipids. Caveolae, specific lipid rafts which concentrate caveolins, harbor signaling molecules and their targets becoming signaling platforms crucial in cell physiology. However, the molecular mechanisms involved in such spatial localization are under debate. Kv1.3 localizes in lipid rafts and participates in the immunological response. We sought to elucidate the mechanisms of Kv1.3 surface targeting, which govern leukocyte physiology. Kv1 channels share a putative caveolin-binding domain located at the intracellular N-terminal of the channel. This motif, lying close to the S1 transmembrane segment, is situated near the T1 tetramerization domain and the determinants involved in the Kvβ subunit association. The highly hydrophobic domain (FQRQVWLLF) interacts with caveolin 1 targeting Kv1.3 to caveolar rafts. However, subtle variations of this cluster, putative ancillary associations and different structural conformations can impair the caveolin recognition, thereby altering channel’s spatial localization. Our results identify a caveolin-binding domain in Kv1 channels and highlight the mechanisms that govern the regulation of channel surface localization during cellular processes.

Caveolin‑1 facilitated KCNA5 expression, promoting breast cancer viability

“…Moreover, cholesterol-depleting experiment showed the decreased expression of KCNA5 and Cav-1 in the plasma membrane, which indicated that channel function, is related to the cholesterol in the membrane microenvironment. Our results were consistent with ones obtained from previous studies in different cell lines ( 48 , 49 ). Some studies have focused on the multiple function of Cav-1 in different cells and tissues, different stages of development, different physiological and pathological processes.…”

Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein kinase C-dependent modulation

“…S2D,H ). To further exclude the involvement of caveolae-dependent internalization, we used a caveolin 1-null (Cav1 − ) HEK-293 cell line 12 . Whether Cav1 − cells were treated with or without MβCD, Kv1.3 always underwent endocytosis in the presence of PMA ( Fig.…”

“…Lipid rafts recruit Kv1.3 in macrophages and in the immunological synapse (IS) of cytotoxic T lymphocytes 11 . The localization of Kv1.3 in rafts and caveolae is dependent on the accessibility of a caveolin-binding domain near the T1 domain and of the Kvβ subunit recognition motif at the N-terminal of the channel 12 . Evidence demonstrates that the control of Kv1.3 surface abundance takes place at multiple stages, balancing forward trafficking mechanisms to the cell membrane and the internalization of fully functional channels 4 13 .…”

The C-terminal domain of Kv1.3 regulates functional interactions with the KCNE4 subunit

“…For example, the Kv7 family as well as the EAG superfamily contain tetramerization domains at their C-termini (Hausammann and Grutter, 2013;Jenke et al, 2003;Schwake et al, 2006), whereas Kv1-Kv6 channels contain their tetramerization domains, named T1, at the N-terminus (Li et al, 1992). The T1 domain and nearby structures participate in associations with Kvβ subunits and caveolin (Gulbis et al, 2000;Perez-Verdaguer et al, 2016a). However, the C-terminus of Kv1 channels does contain important elements for their trafficking and localization.…”