Skip to main content
SpringerLink
Log in

Effects of sodium ions on rat thyrocyte (FRTL-5 cells) swelling- and thyrotropin-activated taurine efflux dependent on cAMP and Epac

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Cellular osmolyte release is important in preventing water accumulation and swelling. However, the signaling pathways that detect volume increase and activate solute efflux are still not fully understood. We investigated efflux activation of the osmolyte taurine which is actively accumulated in rat thyrocytes (FRTL-5). Efflux of accumulated [3H]taurine was stimulated by cellular swelling and thyrotropin (TSH). These effects were significantly diminished in cells having reduced TSH receptor concentrations. Phosphodiesterase inhibitors (IBMX, Rolipram) enhanced both responses. An analog of forskolin (FSK; 7-deacetyl-7-[O-(N-methylpiperazino)-γ-butyryl] dihydrochloride) and an analog of cAMP, specific for activating exchange protein activated directly by cAMP (Epac; 8-(4-chlorophenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate, acetoxymethyl ester), significantly stimulated [3H]taurine efflux. A cAMP analog specific for activating protein kinase A (PKA; N6-benzoyladenosine-3′,5′-cyclic monophosphate, acetoxymethyl ester) had no significant stimulatory effect on [3H]taurine efflux rate. The amiloride analog, 5-(N-ethyl-N-isopropyl)-amiloride, which inhibits a TSH-stimulated Na+/H+ exchanger, enhanced (100 %) and ouabain inhibited (50 %) the TSH-stimulated [3H]taurine efflux rate. The effect of FSK on efflux was strongly potentiated by Na+-free iso-osmotic conditions and by osmolality/cell volume that affected also the db-cAMP-stimulated efflux. The TSH receptors and downstream elements of the signaling pathway comprising adenylyl cyclase, cAMP and Epac appeared to mediate the hormone-induced signal for [3H]taurine efflux from FRTL-5 cells. With less evidence, the cell volume/osmolality-induced [3H]taurine efflux cascade appeared to share some of the hormone signaling elements and to modulate the hormone signaling pathway at two levels through cellular Na+.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Ambesi-Impiombato FS, Parks LAM, Coon HG (1980) Culture of hormone-dependent functional epithelial cells from rat thyroids. Proc Natl Acad Sci USA 77:3455–3459

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Aromataris EC, Roberts ML, Barritt GJ, Rychkov GY (2006) Glucagon activates Ca2+ and Cl− channels in rat hepatocytes. J Physiol 573:611–625

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Blanco G, Mercer RW (1998) Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function. Am J Physiol 275:F633–F650

    PubMed  CAS  Google Scholar 

  • Bourke JR, Matainaho T, Huxham GJ, Manley SW (1987) Cyclic AMP-stimulated fluid transport in thyroid: influence of thyroid stimulators, amiloride and acetazolamide on the dynamics of domes in monolayers of porcine thyroid cells. J Endocrinol 115:19–26

    Article  PubMed  CAS  Google Scholar 

  • Breckler M, Berthouze M, Laurent A, Crozatier B (2011) Rap-linked cAMP signaling Epac proteins: compartmentation, functioning and disease implications. Cell Signal 23:1257–1266

    Article  PubMed  CAS  Google Scholar 

  • Caldwell PC, Keynes RD (1969) The exchange of 22Na between frog sartorius muscle and the bathing medium. In: Stämpfli R, Passow H (eds) Laboratory techniques in membrane biophysics. Springer-Verlag, Berlin, pp 63–68

    Chapter  Google Scholar 

  • Calebiro D, Nikolaev VO, Gagliani MC, de Filippis T, Dees C, Tacchetti C, Persani L, Lohse MJ (2009) Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. PLoS Biol 7:1–25

    Article  CAS  Google Scholar 

  • Calebiro D, Nikolaev VO, Persani L, Lohse MJ (2010) Signaling by internalized G-protein-coupled receptors. Trends in Pharmacol Sci 31:221–228

    Article  CAS  Google Scholar 

  • Cannon CL, Basavappa S, Strange K (1998) Intracellular ionic strength regulates the volume sensitivity of a swelling-activated anion channel. Am J Physiol 275:C416–C422

    PubMed  CAS  Google Scholar 

  • Cetani F, Tonacchera M, Vassart G (1996) Differential effects of NaCl concentration on the constitutive activity of the thyrotropin and the luteinizing hormone/chorionic gonadotropin receptors. FEBS Lett 378:27–31

    Article  PubMed  CAS  Google Scholar 

  • Chepurny OG, Leech CA, Kelley GG, Dzhura I, Dzhura E, Li X, Rindler MJ, Schwede F, Genieser HG, Holz GG (2009) Enhanced Rap1 activation and insulin secretagogue. Properties of an acetoxymethyl ester of an Epac-selective cyclic AMP analog in rat INS-1 cells: studied with 8-pCPT-2′-O-Me-cAMP-AM. J Biol Chem 284:10728–10736

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Conti M, Richter W, Mehats C, Livera G, Park J-Y, Jin C (2003) Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signalling. J Biol Chem 278:5493–5496

    Article  PubMed  CAS  Google Scholar 

  • Dremier S, Milenkovic M, Blancquaerts S, Dunont JE, Doskeland SO, Maenhaut C, Roger PP (2007) Cyclic adenosine 3′,5′-monophosphate (cAMP)-dependent protein kinases, but not exchange proteins directly activated by cAMP (Epac), mediate thyrotropin/cAMP-dependent regulation of thyroid cells. Endocrinology 148:4612–4622

    Article  PubMed  CAS  Google Scholar 

  • Emma F, McManus M, Strange K (1997) Intracellular electrolytes regulate the volume set point of the organic osmolyte/anion channel VSOAC. Am J Physiol 272:C1766–C1775

    PubMed  CAS  Google Scholar 

  • Ericson LE (1981) Exocytosis and endocytosis in the thyroid follicle cell. Mol Cell Endocrinol 22:1–24

    Article  PubMed  CAS  Google Scholar 

  • Fisher SK, Cheema TA, Foster DJ, Heacock AM (2008) Volume-dependent osmolyte efflux from neural tissues: regulation by G-protein-coupled receptors. J Neurochem 106:1998–2014

    PubMed Central  PubMed  CAS  Google Scholar 

  • Fisher SK, Heacock AM, Keep RF, Foster D (2010) Receptor regulation of osmolyte homeostasis in neural cells. J Physiol (London) 588:3355–3364

    Article  CAS  Google Scholar 

  • Fugelli K (2006) G protein-coupled receptor activation of swelling sensitive taurine efflux in rat thyrocytes (FRTL-5 cells). Acta Physiol 187(Suppl 659):P12

    Google Scholar 

  • Gerard C, Gabrion J, Verrier B, Reggio H, Mauchamp J (1985a) Localization of the Na+/K+-ATPase and of an amiloride sensitive Na+ uptake on thyroid epithelial cells. Eur J Cell Biol 38:134–141

    PubMed  CAS  Google Scholar 

  • Gerard C, Verrier B, Mauchamp J (1985b) Effects of prostaglandin E2 and cholera toxin on apical sodium uptake in thyroid epithelial cells: role of cAMP. FEBS Lett 180:9–12

    Article  PubMed  CAS  Google Scholar 

  • Heacock AM, Foster D, Fisher SK (2006) Prostanoid receptors regulate the volume-sensitive efflux of osmolytes from murine fibroblasts via a cyclic AMP-dependent mechanism. J Pharmacol Exp Therapeut 319:963–971

    Article  CAS  Google Scholar 

  • Hoffmann EK, Lambert IH, Pedersen SF (2009) Physiology of cell volume regulation in vertebrates. Physiol Rev 89:193–277

    Article  PubMed  CAS  Google Scholar 

  • Hyzinski-Garcia MC, Rudkouskaya A, Mongin AA (2014) LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes. J Physiol 592(22):4855–4862

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Jhiang SM, Fithian L, Smanik P, McGill J, Tong Q, Mazzaferri EL (1993) Cloning of the human taurine transporter and characterization of taurine uptake in thyroid cells. FEBS 318:139–144

    Article  CAS  Google Scholar 

  • Katritch V, Fenalti G, Abola EE, Roth BL, Cherezov V, Stevens RC (2014) Allosteric sodium in class A GPCR signaling. Trends Biochem Sci 39:233–244

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Kaukel E, Hilz H (1972) Permeation of dibutyryl cAMP into HeLa cells and its conversion to monobutyryl cAMP. Biochem Biophys Res Com 46:1011–1018

    Article  PubMed  CAS  Google Scholar 

  • Kimura T, Van Keymeulen A, Golstein J, Fusco A, Dumont J, Roger P (2001) Regulation of thyroid cell proliferation by TSH and other factors: a critical evaluation of in vitro models. Endocrin Rev 22:631–656

    Article  CAS  Google Scholar 

  • Lambert IH (2004) Regulation of the cellular content of the organic osmolyte taurine in the mammalian cells. Neurochem Res 29:27–63

    Article  PubMed  CAS  Google Scholar 

  • Lang F (2007) Mechanisms and significance of cell volume regulation. J Am Coll Nutr 26:613S–623S

    Article  PubMed  CAS  Google Scholar 

  • Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, Han GW, Roth CB, Heitman LH, Ijzerman AP, Cherezov V, Stevens RC (2012) Structural basis for allosteric regulation of GPCRs by sodium ions. Science (New York) 337:232–236

    Article  CAS  Google Scholar 

  • Mandato E, Catapano R, Ambesi-Impiombato FS, Macchia V (1981) Cyclic nucleotide metabolism in differentiated and undifferentiated epithelial thyroid cells in culture. Biochim Biophys Acta 676:91–100

    Article  PubMed  CAS  Google Scholar 

  • Marcocci C, Grollman EF (1987) Sodium/proton exchange in the maintenance of intracellular pH in FRTL-5 thyroid cells. Endocrinol 123:1705–1711

    Article  Google Scholar 

  • Medina DL, Santisteban P (2000) Thyrotropin-dependent proliferation of in vitro rat thyroid cell systems. Eur J Endocrinol 143:161–178

    Article  PubMed  CAS  Google Scholar 

  • Minieri L, Pivonkova H, Harantova L, Anderova M, Ferroni S (2015) Intracellular Na + inhibits volume-regulated anion channel in rat cortical astrocytes. J Neurochem 132:286–300

    Article  PubMed  CAS  Google Scholar 

  • Mongin AA, Kimelberg HK (2002) ATP potently modulates anion channel-mediatedexitatory amino acid release from cultured astrocytes. Am J Physiol Cell Physiol 283:C569–C578

    Article  PubMed  CAS  Google Scholar 

  • Motais R, Guizouarn H, Garcia-Romeu F (1991) Red cell volume regulation: the pivotal role of ionic strength in controlling swelling-dependent transport systems. Biochim Biophys Acta 1075:169–180

    Article  PubMed  CAS  Google Scholar 

  • Oki N, Takahashi S-I, Hidaka H, Conti M (2000) Short-term feedback regulation of cAMP in FRTL-5 thyroid cells. Role of PDE4D3 phosphodiesterase activation. J Biol Chem 275:10831–10837

    Article  PubMed  CAS  Google Scholar 

  • Qui Z, Dubin AE, Mathur J, Tu B, Reddy K, Miraglia LJ, Reinhardt J, Orth AP, Patapoutian A (2014) SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell 157:447–458

    Article  CAS  Google Scholar 

  • Rosso L, Peteri-Brunbäck B, Poujeol P, Hussy N, Mienville J-M (2003) Vasopressin-induced taurine efflux from rat pituicytes: a potential negative feedback for hormone secretion. J Physiol (London) 554:731–742

    Article  CAS  Google Scholar 

  • Selly DE, Cao CC, Liu Q, Childers SR (2000) Effects of sodium on agonist efficacy for G-protein activation in μ–opioid receptor-transfected CHO cells and rat thalamus. Br J Pharmacol 130:987–996

    Article  Google Scholar 

  • Shennan DB (2008) Swelling-induced taurine transport: relationship with chloride channels, anion-exchangers and other swelling-activated transport pathways. Cell Physiol Biochem 21:15–28

    Article  PubMed  CAS  Google Scholar 

  • Takahashi S-I, Nedashi T, Fukushima T, Umesaki K, Ito Y, Hakuno F, Van Wyk JJ, Conti M (2001) Long-term hormonal regulation of the cAMP-spesific phosphodiesterases in cultured FRTL-5 thyroid cells. Biochim Biophys Acta 1540:68–81

    Article  PubMed  CAS  Google Scholar 

  • Thoroed SM, Soergaard M, Cragoe EJ Jr, Fugelli K (1995) The osmolality-sensitive taurine channel in flounder erythrocytes is strongly stimulated by noradrenaline under hypo-osmotic conditions. J Exp Biol 198:311–324

    PubMed  CAS  Google Scholar 

  • Tørnquist K (1997) Sphingosine 1-phosphate stimulates Na+/H+ exchange in thyroid FRTL-5 cells. Am J Physiol 272:C1052–C1057

    PubMed  Google Scholar 

  • Tramontano D, Ingbar SH (1986) Properties and regulation of the thyrotropin receptor in the FRTL-5 rat thyroid cell line. Endocrinology 118:1945–1946

    Article  PubMed  CAS  Google Scholar 

  • Tsygankova OM, Saavedra A, Rebhun JF, Quilliam LA, Meinkoth (2001) Coordinated regulation of Rap1 and thyroid differentiation by cyclic AMP and protein kinase A. Mol Cell Biol 21:1921–1929

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Vliem MJ, Ponsion B, Schwede F, Pannekoek W-J, Riedl J, Kovistra MRH, Jalink K, Genierser H-G, Bos JL, Rehmann H (2008) 8-pCPT-2′-O-Me-cAMP-AM: an improved Epac-selective cAMP analogue. ChemBioChem 9:2052–2054

    Article  PubMed  CAS  Google Scholar 

  • Voets T, Droogmans G, Raskin G, Eggermont J, Nilius B (1999) Reduced intracellular ionic strength as the initial trigger for activation of endothelial volume-regulated anion channels. Procs Nat Acad Sci USA 96:5298–5303

    Article  CAS  Google Scholar 

  • Voss FK, Ullrich F, Münch J, Lazarow K, Lutter D, Mah N, Andrade-Navarro MA, von Kries JP, Stauber T, Jentsch TJ (2014) Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science 344:634–638

    Article  PubMed  CAS  Google Scholar 

  • Weiss SJ, Philp NJ, Grollman EF (1984) Effect of thyrotropin on I− efflux in FRTL-5 cells mediated by Ca2+. Endocrinology 114:1108

    Article  PubMed  CAS  Google Scholar 

  • Wenzel-Seifert K, Hurt CM, Seifert R (1998) High constitutive activity of the human formyl peptide receptor. J Biol Chem 273:24181–24189

    Article  PubMed  CAS  Google Scholar 

  • Wettstein M, Peters-Regehr T, Kubitz R, Fischer R, Holneicher C, Mönninghoff I, Häussinger D (2000) Release of osmolytes induced by phagocytosis and hormones in rat liver. Am J Physiol Gastrointest Liver Physiol 278:G227–G233

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The author is grateful to Kirsten Ore for excellent technical assistance. Constructive criticism of Dr. T. Berg is deeply acknowledged. This study was supported by Department of Biosciences, University of Oslo.

Author information

Authors and Affiliations

  1. Department of Biosciences, University of Oslo, POBox 1066, Blindern, 0316, Oslo, Norway

    Kjell Fugelli

Authors
  1. Kjell Fugelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kjell Fugelli.

Ethics declarations

Conflict of interest

The author declares no conflict of interest.

Additional information

Handling Editor: E. I. Closs.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fugelli, K. Effects of sodium ions on rat thyrocyte (FRTL-5 cells) swelling- and thyrotropin-activated taurine efflux dependent on cAMP and Epac. Amino Acids 48, 763–777 (2016). https://doi.org/10.1007/s00726-015-2124-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-015-2124-9

Keywords

Search

Navigation