Molecular Proximity of Kv1.3 Voltage-gated Potassium Channels and β1-Integrins on the Plasma Membrane of Melanoma Cells

Abstract

Tumor cell membranes have multiple components that participate in the process of metastasis. The present study investigates the physical association of β1-integrins and Kv1.3 voltage-gated potassium channels in melanoma cell membranes using resonance energy transfer (RET) techniques. RET between donor-labeled anti–β1-integrin and acceptor-labeled anti-Kv1.3 channels was detected on LOX cells adherent to glass and fibronectin-coated coverslips. However, RET was not observed on LOX cells in suspension, indicating that molecular proximity of these membrane molecules is adherence-related. Several K+ channel blockers, including tetraethylammonium, 4-aminopyridine, and verapamil, inhibited RET between β1-integrins and Kv1.3 channels. However, the irrelevant K+ channel blocker apamin had no effect on RET between β1-integrins and Kv1.3 channels. Based on these findings, we speculate that the lateral association of Kv1.3 channels with β1-integrins contributes to the regulation of integrin function and that channel blockers might affect tumor cell behavior by influencing the assembly of supramolecular structures containing integrins.

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

“…Inhibition of K ϩ channels and the subsequent activation of voltagegated Ca 2ϩ channels by depolarization is one of the important mechanisms by which hormone production is regulated in these cell types (305). A noninactivating, ACTH-and angiotensin II-sensitive potassium current of bovine fasciculata cells (IAC) was already described in FIG. 6. Mechanistic model of TREK-1 regulation in the systemic circulation.…”

“…Overexpression of different potassium channels has been found in different malignant cells, and their activity has been related to tumor progression (6,79,105,262,353). Ether-á -go-go potassium channel was even considered as a highly significant tumor marker with diagnostic and possibly also with therapeutic relevance (307).…”

ICln, a Novel Integrin αIIbβ3-Associated Protein, Functionally Regulates Platelet Activation

“…Similarly, ligand binding to integrins or integrin clustering modulates potassium currents, leading to hyperpolarization of monocytes and enhanced Ca 2ϩ influx (30). Integrin co-localization with ion channels has been observed in LOX tumor cells where ␤ 1 -integrins associate laterally with potassium channels during adhesion contributing to the regulation of integrin function in these cells (31). Co-localization of ␤ 1 -integrins with the ␣-subunits of Na,K-ATPase, the epithelial sodium channel, and the voltage-activated calcium channel has also been shown (23).…”

Ion channels and anti-cancer immunity

“…Kv1.3, KCa3.1 and CRAC channels are integral components of the IS signalosome [7,10,21 -23]. These channels promote outside -in signalling, provide localized and polarized regulation of membrane potential and calcium signalling [24,25], modulate K þ dependence of integrin function [26,27], and serve to tether the channels to the T-cell receptor complex and intracellular signalling molecules via interactions with hDlg/SAP-97, p56lck tyrosine kinase [28], ZIP1 [10] and PSD-95 [29].…”