Functional and molecular identification of intermediate-conductance Ca²⁺-activated K⁺ channels in breast cancer cells: association with cell cycle progression

Abstract

Ahidouch, Halima Ouadid, Morad Roudbaraki, Philippe Delcourt, Ahmed Ahidouch, Nathalie Joury, and Natalia Prevarskaya. Functional and molecular identification of intermediate-conductance Ca 2ϩ -activated K ϩ channels in breast cancer cells: association with cell cycle progression. Am J Physiol Cell Physiol 287: C125-C134, 2004. First published February 25, 2004 10.1152/ ajpcell.00488.2003.-We have previously reported that the hEAG K ϩ channels are responsible for the potential membrane hyperpolarization that induces human breast cancer cell progression into the G1 phase of the cell cycle. In the present study, we evaluate the role and functional expression of the intermediate-conductance Ca 2ϩ -activated K ϩ channel, hIK1-like, in controlling cell cycle progression. Our results demonstrate that hIK1 current density increased in cells synchronized at the end of the G1 or S phase compared with those in the early G1 phase. This increased current density paralleled the enhancement in hIK1 mRNA levels and the highly negative membrane potential. Furthermore, in cells synchronized at the end of G1 or S phases, basal cytosolic Ca 2ϩ concentration ([Ca 2ϩ ]i) was also higher than in cells arrested in early G1. Blocking hIK1 channels with a specific blocker, clotrimazole, induced both membrane potential depolarization and a decrease in the [Ca 2ϩ ]i in cells arrested at the end of G1 and S phases but not in cells arrested early in the G1 phase. Blocking hIK1 with clotrimazole also induced cell proliferation inhibition but to a lesser degree than blocking hEAG with astemizole. The two drugs were essentially additive, inhibiting MCF-7 cell proliferation by 82% and arresting Ͼ90% of cells in the G1 phase. Thus, although the progression of MCF-7 cells through the early G1 phase is dependent on the activation of hEAG K ϩ channels, when it comes to G1 and checkpoint G1/S transition, the membrane potential appears to be primarily dependent on the hIK1-activity level. breast cancer; calcium-activated potassium channels; proliferation THERE IS GOOD EVIDENCE from several cell lines that membrane potential in the early G1 phase is depolarized, and the progression through G1 into the S phase is accompanied by a hyperpolarization of the membrane potential. The blockade of K ϩ

Renal fibrosis is attenuated by targeted disruption of K Ca 3.1 potassium channels

“…Ouadid-Ahidouch et al have recently reported in a cell culture study, that in MCF-7 breast cancer cells this mechanism is critically dependent on the activity of K Ca 3.1. Conversely, blockade of these channels diminished [Ca 2ϩ ] i , halted cell cycle progression and suppressed breast cancer cell proliferation (25). Here, we demonstrate that selective K Ca 3.1 inhibition with TRAM-34 is able to suppress the proliferation of renal fibroblasts in a dose-dependent manner.…”

“…Whereas the first directly mediate Ca 2ϩ inflow, the latter regulate membrane potential and thus provide the driving force for Ca 2ϩ entry (13). In particular, the intermediate-conductance K Ca (K Ca 3.1) has been shown to play an important role in promoting mitogenesis in several tissues such as the endothelium (15,16), vascular smooth muscle (17)(18)(19), and T lymphocytes (20) as well as in several cell lines including A7r5 neonatal aortic smooth muscle cells (21), 10T1/2-MRF4 myogenic fibroblasts (22,23), HMEC-1 dermal endothelial cells (15), and some cancer cell lines (24,25).…”

Migration-associated secretion of melanoma inhibitory activity at the cell rear is supported by KCa3.1 potassium channels

“…Since Ca 2+ -activated K + channels are expressed in most (if not all) cells possessing the ability to migrate, including leukocytes and many tumor cells, their roles in cell migration warrant close examination [18,[57][58][59][60][61][62][63]. In previous studies, it was described that the KCa3.1 channel is highly expressed in malignant melanoma cells [19].…”

Diversity of Ion Channels in Human Bone Marrow Mesenchymal Stem Cells from Amyotrophic Lateral Sclerosis Patients

“…Ion channels are widely expressed in proliferative cells which can modulate the proliferation of cells by affecting the cell cycle (MacFarlane & Sontheimer, 2000;Ouadid-Ahidouch et al, 2004;Biagiotti et al, 2006). Recent studies from our group and others have demonstrated that multifunctional ion channels are heterogeneously expressed in various species of MSCs (Li et al, 2005;Deng et al, 2006;Li et al, 2006;Park et al, 2007;Tao et al, 2007).…”