Calcium-gated K+ channels of the KCa1.1- and KCa3.1-type couple intracellular Ca2+ signals to membrane hyperpolarization in mesenchymal stromal cells from the human adipose tissue

Abstract

Electrogenesis in mesenchymal stromal cells (MSCs) remains poorly understood. Little is known about ion channels active in resting MSCs and activated upon MSC stimulation, particularly, by agonists mobilizing Ca in the MSC cytoplasm. A variety of Ca-gated ion channels may couple Ca signals to polarization of the plasma membrane. Here, we studied MSCs from the human adipose tissue and found that in cells responsive to ATP and adenosine with Ca transients or exhibiting spontaneous Ca oscillations, Ca bursts were associated with hyperpolarization mediated by Ca-gated K channels. The expression analysis revealed transcripts for KCNMA1 and KCNN4 genes encoding for Ca-activated K channels of large (K1.1) and intermediate (K3.1) conductance, respectively. Moreover, transcripts for the Ca-gated cation channel TRPM4 and anion channels Ano1, Ano2, and bestrophin-1, bestrophin-3, and bestrophin-4 were revealed. In all assayed MSCs, a rise in cytosolic Ca stimulated K currents that were inhibited with iberiotoxin. This suggested that K1.1 channels are invariably expressed in MSCs. In ATP- and adenosine-responsive cells, iberiotoxin and TRAM-34 diminished electrical responses, implicating both K1.1 and K3.1 channels in coupling agonist-dependent Ca signals to membrane voltage. Functional tests pointed at the existence of two separate MSC subpopulations exhibiting Ca-gated anion currents that were mediated by Ano2-like and bestrophin-like anion channels, respectively. Evidence for detectable activity of Ano1 and TRPM4 was not obtained. Thus, K1.1 channels are likely to represent the dominant type of Ca-activated K channels in MSCs, which can serve in concert with K3.1 channels as effectors downstream of G-protein-coupled receptor (GPCR)-mediated Ca signaling.

Mesenchymal stem cell differentiation: Control by calcium‐activated potassium channels

“…Such functional association of V m , K Ca (s), and [Ca 2+ ] i can result in [Ca 2+ ] i oscillations with mathematical modeling indicating that K Ca activity plays a central role (Catacuzzeno et al, ). Indeed, in direct support of our model, rise in [Ca 2+ ] i in adMSC hyperpolarized V m via K Ca activity (Catacuzzeno et al, ; Tarasov et al, ).…”

“…Consistently, pharmacologically blocking NCX abolished [Ca 2+ ] i oscillations (Kawano et al, 2003;Ye, 2010 (Catacuzzeno et al, 2012;Tarasov et al, 2017).…”

Arachidonic acid hyperpolarizes mesenchymal stromal cells from the human adipose tissue by stimulating TREK1 K+ channels

“…Here we studied electrogenic effects of AA on MSCs from the human adipose tissue and found this fatty acid to strongly hyperpolarize all cells tested (Figure 1(a,b)) by increasing their permeability to K + ions (Figure 1(c,d)). Among likely mechanisms, we particularly considered the possibility that AA could activate Ca 2+ entry channels [32], thereby elevating cytosolic Ca 2+ and stimulating Ca 2+ -gated K + channels, which have been identified in MSCs from different sources, including the human adipose tissue [33,34]. However, these Ca 2+ -gated K + channels were blocked by TEA [33,34], and therefore their contribution to the TEA-independent electrogenic effects of AA on MSCs (Figure 3(a,b)) might not be essential.…”

“…Among likely mechanisms, we particularly considered the possibility that AA could activate Ca 2+ entry channels [32], thereby elevating cytosolic Ca 2+ and stimulating Ca 2+ -gated K + channels, which have been identified in MSCs from different sources, including the human adipose tissue [33,34]. However, these Ca 2+ -gated K + channels were blocked by TEA [33,34], and therefore their contribution to the TEA-independent electrogenic effects of AA on MSCs (Figure 3(a,b)) might not be essential. This inference was supported by the observation that 10-30 µM AA never elevated cytosolic Ca 2+ to the level ( Figure 1S) required for sufficient MSC hyperpolarization associated with the activation of Ca 2+ -gated K + channels [34].…”

Expression of Ion Channels in Perivascular Stem Cells derived from Human Umbilical Cords

“…K + channels have important roles in maintaining normal functions and physiological homeostasis in various cell types as well as regulating the cell cycle, differentiation, and maturation (Kawano et al, 2002). Although several studies have characterized the electrophysiological properties of MSCs and pluripotent stem cells (Heubach et al, 2003; Li et al, 2005; Wang et al 2005; Bai et al, 2007; Park et al, 2007; Jiang et al, 2010; Park et al., 2013; Tarasov et al, 2017), the expression and function of ion channels in HUCPVCs have not been studied. Therefore, for therapeutic applications, we need to investigate not only the multi-lineage differentiation capacity, but also the electrophysiological properties of K + channels in HUCPVCs.…”