Skip to main content

Advertisement

SpringerLink
Log in

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

  • Signaling and cell physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

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 Ca2+ in the MSC cytoplasm. A variety of Ca2+-gated ion channels may couple Ca2+ 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 Ca2+ transients or exhibiting spontaneous Ca2+ oscillations, Ca2+ bursts were associated with hyperpolarization mediated by Ca2+-gated K+ channels. The expression analysis revealed transcripts for KCNMA1 and KCNN4 genes encoding for Ca2+-activated K+ channels of large (KCa1.1) and intermediate (KCa3.1) conductance, respectively. Moreover, transcripts for the Ca2+-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 Ca2+ stimulated K+ currents that were inhibited with iberiotoxin. This suggested that KCa1.1 channels are invariably expressed in MSCs. In ATP- and adenosine-responsive cells, iberiotoxin and TRAM-34 diminished electrical responses, implicating both KCa1.1 and KCa3.1 channels in coupling agonist-dependent Ca2+ signals to membrane voltage. Functional tests pointed at the existence of two separate MSC subpopulations exhibiting Ca2+-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, KCa1.1 channels are likely to represent the dominant type of Ca2+-activated K+ channels in MSCs, which can serve in concert with KCa3.1 channels as effectors downstream of G-protein-coupled receptor (GPCR)-mediated Ca2+ signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Bai X, Ma J, Pan Z et al (2007) Electrophysiological properties of human adipose tissue-derived stem cells. Am J Physiol Cell Physiol 293:1539–1550

    Article  Google Scholar 

  2. Barradas AM, Fernandes HA, Groen N et al (2012) A calcium-induced signaling cascade leading to osteogenic differentiation of human bone marrow-derived mesenchymal stromal cells. Biomaterials 33:3205–3215

    Article  CAS  PubMed  Google Scholar 

  3. Becchetti A (2011) Ion channels and transporters in cancer. 1. Ion channels and cell proliferation in cancer. Am J Physiol Cell Physiol 301:255–265

    Article  Google Scholar 

  4. Bertuccio CA, Devor DC (2015) Intermediate conductance, Ca2+-activated K+ channels: a novel target for chronic renal diseases. Front Biol 10:52–60

    Article  CAS  Google Scholar 

  5. Blackiston DJ, McLaughlin KA, Levin M (2009) Bioelectric controls of cell proliferation ion channels, membrane voltage and the cell cycle. Cell Cycle 8:3527–3536

    Article  CAS  PubMed  Google Scholar 

  6. Campagnoli C, Roberts IA, Kumar S et al (2001) Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 98:2396–2402

    Article  CAS  PubMed  Google Scholar 

  7. Capiod T (2011) Cell proliferation, calcium influx and calcium channels. Biochimie 93:2075–2079

    Article  CAS  PubMed  Google Scholar 

  8. Catacuzzeno L, Caramia M, Sforna L et al (2015) Reconciling the discrepancies on the involvement of large-conductance Ca2+-activated K channels in glioblastoma cell migration. Front Cell Neurosci 9:152

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chandy KG, Wulff H, Beeton C et al (2004) K+ channels as targets for specific immunomodulation. Trends Pharmacol Sci 25:280–289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ciciarello M, Zini R, Rossi L, Salvestrini V, Ferrari D, Manfredini R, Lemoli RM (2013) Extracellular purines promote the differentiation of human bone marrow-derived mesenchymal stem cells to the osteogenic and adipogenic lineages. Stem Cells Dev 22(7):1097–1111

    Article  CAS  PubMed  Google Scholar 

  11. Cheng H, Feng JM, Figueiredo ML et al (2010) Transient receptor potential melastatin type 7 channel is critical for the survival of bone marrow derived mesenchymal stem cells. Stem Cells Dev 19:1393–1403

    Article  CAS  PubMed  Google Scholar 

  12. Cherkashin AP, Kolesnikova AS, Tarasov MV et al (2016) Expression of calcium-activated chloride channels Ano1 and Ano2 in mouse taste cells. Pflugers Arch 468:305–319

    Article  CAS  PubMed  Google Scholar 

  13. Cidad P, Jimenez-Perez L, Garcia-Arribas D et al (2012) Kv1.3 channels can modulate cell proliferation during phenotypic switch by an ion-flux independent mechanism. Arterioscler Thromb Vasc Biol 32:1299–1307

    Article  CAS  PubMed  Google Scholar 

  14. Clapham DE (2007) Calcium signaling. Cell 131:1047–1058

    Article  CAS  PubMed  Google Scholar 

  15. De La Fuente R, Namkung W, Mills A et al (2008) Small-molecule screen identifies inhibitors of a human intestinal calcium-activated chloride channel. Mol Pharmacol 73:758–768

    Article  CAS  PubMed  Google Scholar 

  16. Deng XL, Sun HY, Lau CP, Li GR (2006) Properties of ion channels in rabbit mesenchymal stem cells from bone marrow. Biochem Biophys Res Commun 348:301–309

    Article  CAS  PubMed  Google Scholar 

  17. Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement, Cytotherapy 8:315–317

    CAS  PubMed  Google Scholar 

  18. Ferrari D, Gulinelli S, Salvestrini V et al (2011) Purinergic stimulation of human mesenchymal stem cells potentiates their chemotactic response to CXCL12 and increases the homing capacity and production of proinflammatory cytokines. Exp Hematol 39:360–374

    Article  CAS  PubMed  Google Scholar 

  19. Forostyak O, Forostyak S, Kortus S et al (2016) Physiology of Ca2+ signalling in stem cells of different origins and differentiation stages. Cell Calcium 59:57–66

    Article  CAS  PubMed  Google Scholar 

  20. Grgic I, Eichler P, Heinau et al. (2005) Selective blockade of the intermediate-conductance Ca2+-activated K+ channel suppresses proliferation of microvascular and macrovascular endothelial cells and angiogenesis in vivo. Arterioscler Thromb Vasc Biol 25:704–709

  21. Guinamard R, Salle L, Simard C (2011) The non-selective monovalent cationic channels TRPM4 and TRPM5. In: Islam MS (ed) Transient receptor potential channels. Springer, Netherlands, pp. 147–171

    Chapter  Google Scholar 

  22. Guinamard, R., Hof, T. and Del Negro, C. A. (2014) The TRPM4 channel inhibitor 9-phenanthrol. Br J Pharmacol 1600–1613

  23. Hartzell HC, Qu Z, Yu K, Xiao Q, Chien LT (2008) Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies. Physiol Rev 88:639–672

    Article  CAS  PubMed  Google Scholar 

  24. Heubach JF, Graf EM, Leutheuser J et al (2004) Electrophysiological properties of human mesenchymal stem cells. J Physiol Lond 554:659–672

    Article  CAS  PubMed  Google Scholar 

  25. Im GI, Shin YW, Lee KB (2005) Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthr Cartil 13:845–853

    Article  PubMed  Google Scholar 

  26. Ishii H, Nakajo K, Yanagawa Y, Kubo Y (2010) Identification and characterization of Cs+ -permeable K+ channel current in mouse cerebellar Purkinje cells in lobules 9 and 10 evoked by molecular layer stimulation. Eur J Neurosci 32:736–748

    Article  PubMed  Google Scholar 

  27. Jackson WF (2005) Potassium channels and proliferation of vascular smooth muscle cells. Circ Res 97:1211–1212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jensen BS, Hertz M, Christophersen P, Madsen LS (2002) The Ca2+-activated K+ channel of intermediate conductance: a possible target for immune suppression. Expert Opin Ther Targets 6:623–636

    Article  CAS  PubMed  Google Scholar 

  29. Jia X, Yang J, Song W (2013) Involvement of large conductance Ca2+-activated K+ channel in laminar shear stress-induced inhibition of vascular smooth muscle cell proliferation. Pflugers Arch 465:221–232

    Article  CAS  PubMed  Google Scholar 

  30. Kalinina NI, Sysoeva VY, Rubina KA et al (2011) Mesenchymal stem cells in tissue growth and repair. Acta Nat 3:30–37

    CAS  Google Scholar 

  31. Kawano S, Otsu K, Kuruma A et al (2006) ATP autocrine/paracrine signaling induces calcium oscillations and NFAT activation in human mesenchymal stem cells. Cell Calcium 39:313–324

    Article  CAS  PubMed  Google Scholar 

  32. Kawano S, Shoji S, Ichiose S et al (2002) Characterization of Ca2+ signaling pathways in human mesenchymal stem cells. Cell Calcium 32:165–174

    Article  CAS  PubMed  Google Scholar 

  33. Kawashima N (2012) Characterisation of dental pulp stem cells: a new horizon for tissue regeneration? Arch Oral Biol 57:1439–1458

    Article  PubMed  Google Scholar 

  34. Kolesnikov SS, Margolskee RF (1998) Extracellular K+ activates a K+- and H+-permeable conductance in frog taste receptor cells. J Physiol Lond 1:415–432

    Article  Google Scholar 

  35. Kotova PD, Sysoeva VY, Rogachevskaja OA et al (2014) Functional expression of adrenoreceptors in mesenchymal stromal cells derived from the human adipose tissue. Biochim Biophys Acta 1843:1899–1908

    Article  CAS  PubMed  Google Scholar 

  36. Kraft R, Krause P, Jung S et al (2003) BK channel openers inhibit migration of human glioma cells. Pflugers Arch 446:248–255

    Article  CAS  PubMed  Google Scholar 

  37. Kunzelmann K (2015) TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca2+ and cell volume. Trends Biochem Sci 40:535–543

    Article  CAS  PubMed  Google Scholar 

  38. Latorre R, Gonzalez C, Rojas P (2013) Signal transduction-dependent channels. In: Pfaff DW (ed) Neuroscience in the 21st century, Springer Science+Business Media, LLC, pp 81–107

  39. Le Blanc K, Mougiakakos D (2012) Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 12:383–396

    Article  CAS  PubMed  Google Scholar 

  40. Li GR, Deng XL, Sun H et al (2006) Ion channels in mesenchymal stem cells from rat bone marrow. Stem Cells 24:1519–1528

    Article  CAS  PubMed  Google Scholar 

  41. Milenkovic VM, Soria RB, Aldehni F, Schreiber R, Kunzelmann K (2009) Functional assembly and purinergic activation of bestrophins. Pflugers Arch 458:431–441

    Article  CAS  PubMed  Google Scholar 

  42. Nelson P, Ngoc Tran TD, Zhang H et al (2013) Transient receptor potential melastatin 4 channel controls calcium signals and dental follicle stem cell differentiation. Stem Cells 31:167–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Park KS, Jung KH, Kim SH et al (2007) Functional expression of ion channels in mesenchymal stem cells derived from umbilical cord vein. Stem Cells 25:2044–2052

    Article  CAS  PubMed  Google Scholar 

  44. Pifferi S, Dibattista M, Menini A (2009) TMEM16B induces chloride currents activated by calcium in mammalian cells. Pflugers Arch 458:1023–1038

    Article  CAS  PubMed  Google Scholar 

  45. Pillozzi S, Becchetti A (2012) Ion channels in hematopoietic and mesenchymal stem cells. Stem Cells Int 2012. Doi:10.1155/2012/217910

  46. Petersen OH, Maruyama Y (1984) Calcium-activated potassium channels and their role in secretion. Nature 307:693–696

    Article  CAS  PubMed  Google Scholar 

  47. Petersen OH (1992) Stimulus-secretion coupling: cytoplasmic calcium signals and the control of ion channels in exocrine acinar cells. J Physiol 448:1–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Resende RR, Andrade LM, Oliveira AG et al (2013) Nucleoplasmic calcium signaling and cell proliferation: calcium signaling in the nucleus. Cell Commun Signal 11:14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rizzuto R, Pozzan T (2006) Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 86:369–408

    Article  CAS  PubMed  Google Scholar 

  50. Salkoff L, Butler A, Ferreira G et al (2006) High-conductance potassium channels of the SLO family. Nat Rev Neurosci 7:921–931

    Article  CAS  PubMed  Google Scholar 

  51. Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T, Muroi K, Ozawa K (2007) Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 109:228–234

    Article  CAS  PubMed  Google Scholar 

  52. Scarfi S (2014) Purinergic receptors and nucleotide processing ectoenzymes: their roles in regulating mesenchymal stem cell functions. World J. Stem Cells 6:153–162

    Google Scholar 

  53. Scudieri P, Sondo E, Ferrera L et al (2012) The anoctamin family: TMEM16A and TMEM16B as calcium-activated chloride channels. Exp Physiol 97:177–183

    Article  CAS  PubMed  Google Scholar 

  54. Sheng J-Z, Braun AP (2007) Small- and intermediate-conductance Ca2+-activated K+ channels directly control agonist-evoked nitric oxide synthesis in human vascular endothelial cells. Am J Physiol Cell Physiol 293:C458–C467

    Article  CAS  PubMed  Google Scholar 

  55. Spees JL, Lee RH, Gregory CA (2016) Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther 7:125

    Article  PubMed  PubMed Central  Google Scholar 

  56. Stocker M (2004) Ca2+-activated K+ channels: molecular determinants and function of the SK family. Nat Rev Neurosci 5:758–770

    Article  CAS  PubMed  Google Scholar 

  57. Sundelacruz S, Levin M, Kaplan DL (2009) Role of membrane potential in the regulation of cell proliferation and differentiation. Stem Cell Rev 5:231–246

    Article  PubMed  Google Scholar 

  58. Tang JM, Yuan J, Li Q et al (2012) Acetylcholine induces mesenchymal stem cell migration via Ca2+/PKC/ERK1/2 signal pathway. J Cell Biochem 113:2704–2713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tao R, Lau CP, Tse HF, Li GR (2007) Functional ion channels in mouse bone marrow mesenchymal stem cells. Am J Physiol Cell Physiol 293:1561–1567

    Article  Google Scholar 

  60. Tao R, Sun HY, Lau CP et al (2011) Cyclic ADP ribose is a novel regulator of intracellular Ca2+ oscillations in human bone marrow mesenchymal stem cells. J Cell Mol Med 15:2684–2696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Toro L, Li M, Zhang Z et al (2014) MaxiK channel and cell signaling. Pflugers Arch 466:875–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tran TD, Zolochevska O, Figueiredo ML et al (2014) Histamine-induced Ca2+ signalling is mediated by TRPM4 channels in human adipose-derived stem cells. Biochem J 463:123–134

    Article  CAS  PubMed  Google Scholar 

  63. Vandael DH, Marcantoni A, Mahapatra S et al (2010) Cav1.3 and BK channels for timing and regulating cell firing. Mol Neurobiol 42:185–198

    Article  CAS  PubMed  Google Scholar 

  64. Wang SP, Wang JA, Luo RH et al (2008) Potassium channel currents in rat mesenchymal stem cells and their possible roles in cell proliferation. Clin Exp Pharmacol Physiol 35:1077–1084

    Article  CAS  PubMed  Google Scholar 

  65. Wei AD, Gutman GA, Aldrich R et al (2005) International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium activated potassium channels. Pharmacol Rev 57:463–472

    Article  CAS  PubMed  Google Scholar 

  66. Wei J-F, Wei L, Zhou X et al (2008) Formation of Kv2.1-FAK complex as a mechanism of FAK activation, cell polarization and enhanced motility. J Cell Physiol 217:544–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ye B (2010) Ca2+ oscillations and its transporters in mesenchymal stem cells. Physiol Res 59:323–329

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Russian Science Foundation (grants 14-14-00687) and the Russian Foundation for Basic Research (grant 14-04-01711a).

Author information

Authors and Affiliations

  1. Institute of Cell Biophysics, Russian Academy of Sciences, Institutional Street 3, Pushchino, Moscow Region, Russia, 142290

    Michail V. Tarasov, Marina F. Bystrova, Polina D. Kotova, Olga A. Rogachevskaja & Stanislav S. Kolesnikov

  2. Department of Biochemistry and Molecular Medicine, Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, Russia

    Veronika Y. Sysoeva

Authors
  1. Michail V. Tarasov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marina F. Bystrova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Polina D. Kotova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Olga A. Rogachevskaja
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Veronika Y. Sysoeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stanislav S. Kolesnikov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stanislav S. Kolesnikov.

Electronic supplementary material

ESM 1

(PDF 349 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tarasov, M.V., Bystrova, M.F., Kotova, P.D. et al. 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. Pflugers Arch - Eur J Physiol 469, 349–362 (2017). https://doi.org/10.1007/s00424-016-1932-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-016-1932-4

Keywords

Search

Navigation