Emerging roles for multifunctional ion channel auxiliary subunits in cancer

Figures

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  Fig. 1. Voltage-gated Ca2+ channel auxiliary subunits. Voltage-gated Ca2+ channels (VGCCs) are composed of a conducting α1 subunit accompanied and functionally modulated by Cavβ, α2δ and Cavγ subunits [20]. α1 consists of four domains (domains I-IV), each consisting of six segments (S1-S6). The voltage-sensing domain is found within S4 of each domain and the pore consists of the P-loop found between S5-6 of each domain. Cavβ modulates Ca2+ influx via binding the DI-DII linker of α1. Cavβs are also involved in regulating gene expression and endocytosis [22,[36], [37], [38],40,44]. α2δ subunits are extracellular proteins that remain associated to the membrane via a GPI-anchor [54]. α2δ subunits are involved in synaptogenesis [65]. Cavγ subunits are four-pass transmembrane proteins also involved in cervical ganglion neurite outgrowth and synaptogenesis [108,109].

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  Fig. 2. K+ channel auxiliary subunits. (A) Voltage-gated K+ channels (VGKCs). The conducting subunit, Kvα forms tetramers within the membrane that are accompanied and functionally modulated by four Kvβs (for Kv1), four KChIPs (for Kv4) or two KCNEs (Kv7.1) [[119], [120], [121], [122]]. The function of Kvβ is modulated by pyridine nucleotides [143]. KChIPs are involved in regulating gene expression [173]. (B) Large conductance Ca2+-activated K+ (BK) channels. BK channels consist of a K+-conducting, seven-pass (S0-S6) membrane protein subunit (BKα/Slo) accompanied and modulated by dual-pass BKβ and BKγ [182,187]. S0 of BKα is required for interaction with BKβ, S4 is involved in voltage-sensing, the pore region is formed by the linker of S5-6 and an enlarged C-terminus containing two RCK (regulator of conductance of K+) domains sense intracellular Ca2+ [330]. (C) Inwardly rectifying K+ (Kir) channels. Tetrameric Kir6 subunits, containing the K+-conducting pore, are functionally regulated at the membrane by 17-pass SUR subunits (1:1 stoichiometry), which confer ATP-sensitivity onto Kir6 via NBDs (nucleotide binding domains) [196]. Kir1-4 can be bound and modulated by various C-terminal…

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  Fig. 3. Voltage-gated Na+ channel auxiliary subunits. Voltage-gated Na+ channels (VGSCs) contain a conducting Navα subunit and auxiliary Navβ subunits. Navα consists of four domains (domains I-IV), each containing six segments (S1-S6). The voltage-sensing domain is found within S4 of each domain and the pore consists of the P-loop found between S5-6 of each domain. Navβs function as cell adhesion molecules via an extracellular immunoglobulin domain [238,239,332]. Navβs also induce neurite outgrowth and migration [245] and the intracellular domain of Navβ2 has putative transcription regulation function [248].

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  Fig. 4. Cl− channel auxiliary subunits. (A) CLCs are a subfamily of voltage-sensitive Cl− channels and transporters found at the plasma membrane and internal membranes [13]. Barttin modulates ClC-K, GlialCAM modulates ClC-2 and Ostm1 modulates the intracellular ClC-7 transporter [264,266,267]. CLCs are composed of eighteen helical domains and two C-terminal cystathionine-β-synthase (CBS) domains which facilitate dimerization [333]. Depicted is the plasma membrane ClC-2 which interacts with single-pass GlialCAM, the only ClC auxiliary subunit implicated in cancer [264]. GlialCAM can also function as a cell adhesion molecule [268]. (B) Two separate CaCC conducting subunits exist- TMEM16 and Bestrophin. Depicted is eight-pass TMEM16 A which is modulated directly by secreted CLCA1 and indirectly by single-pass CLCA2 [303,305]. CLCA2 stimulates Ca2+ store replenishment by interacting with Orai1 and STIM1 [305].

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  Fig. 5. Involvement of ion channel auxiliary subunits in different stages of tumour progression. A number of different ion channel auxiliary subunits are up- or down-regulated in cancer cells promoting proliferation, reducing apoptosis and differentiation. Other auxiliary subunits have been shown to regulate angiogenesis, invasion, and metastasis, thus promoting tumour progression. Finally, ion channel auxiliary subunits may also play a role in chemo/radioresistance, underscoring the potential importance of these proteins in relation to therapeutic intervention.