Advertisement

European Biophysics Journal

, Volume 40, Issue 9, pp 1029–1042 | Cite as

Effect of lithium on the electrical properties of polycystin-2 (TRPP2)

  • María del Rocío Cantero
  • Horacio F. CantielloEmail author
Original Paper

Abstract

Polycystin-2 (PC2, TRPP2) is a TRP-type, non-selective cation channel whose dysfunction is implicated in changes in primary cilium structure and genesis of autosomal dominant polycystic kidney disease (ADPKD). Lithium (Li+) is a potent pharmaceutical agent whose effect on cell function is largely unknown. In this work, we explored the effect of Li+ on PC2 channel function. In vitro translated PC2 was studied in a lipid bilayer reconstitution system exposed to different chemical conditions such as Li+ or K+ chemical gradients and different symmetrical concentrations of either cation. Li+ inhibited PC2 function only from the external side, by decreasing the single-channel conductance and modifying the reversal potential consistent with both permeability to and blockage of the channel. When a chemical gradient was imposed, the PC2 single-channel conductance was 144 pS and 107 pS for either K+ or Li+, respectively. Data were analysed in terms of the Goldman–Hodgkin–Katz approximation and energy models based on absolute rate theory to understand the mechanism(s) of Li+ transport and blockage of PC2. The 2S3B model better explained the findings, including saturation, anomalous mole fraction, non-linearity of the current–voltage curves under bi-ionic conditions and concentration dependence of permeability ratios. The data indicate that Li+ modifies PC2 channel function, whose effect unmasks a high-affinity binding site for this ion, and an intrinsic asymmetry in the pore structure of the channel. The findings provide insights into possible mechanism(s) of Li+ regulation of ciliary length and dysfunction mediated by this cation.

Keywords

TRP channels Absolute rate theory Anomalous molar fraction Primary cilia 

Abbreviations

2S3B

Two-site three-barrier model

3S4B

Three-site four-barrier model

ADPKD

Autosomal dominant polycystic kidney disease

ENaC

Epithelial sodium channel

GHK

Goldman–Hodgkin–Katz

GHKm

Modified Goldman–Hodgkin–Katz

GHKo

Original Goldman–Hodgkin–Katz

Hepes

4-(2-Hydroxyethyl)-1-piperazineethanesulphonic acid

hST

Human syncytiotrophoblast

PC2

Polycystin-2 (TRPP2)

Perm-selectivity

Permeation selectivity

POPC

Phosphatidyl-choline

POPE

Phosphatidyl-ethanolamine

TM

Transmembrane

TRP

Transient receptor potential

TRPC1

TRP canonical type-1

I/V

Current–voltage relationship

Vrev

Reversal potential

Notes

Acknowledgments

The authors are members of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina. The authors are deeply grateful to Dr. Patricia Bonazzola, for constant and unconditional support and encouragement, and Sumit Lal, for excellent technical support. The authors gratefully acknowledge partial support of this study by NIH ARRA award DK077079.

Supplementary material

249_2011_715_MOESM1_ESM.pdf (321 kb)
Supplementary material 1 (PDF 321 kb)

References

  1. Almers W, McCleskey EW (1984) Non-selective conductance in calcium channels of frog muscle: calcium selectivity in a single-file pore. J Physiol 353:585–608PubMedGoogle Scholar
  2. Alvarez O, Villarroel A, Eisenman G (1992) Calculation of ion currents from energy profiles and energy profiles from ion currents in multibarrier, multisite, multioccupancy channel model. Methods Enzymol 207:816–854PubMedCrossRefGoogle Scholar
  3. Bai CX, Giamarchi A, Rodat-Despoix L, Padilla F, Downs T, Tsiokas L, Delmas P (2008) Formation of a new receptor-operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits. EMBO Rep 9:472–479PubMedCrossRefGoogle Scholar
  4. Cantiello HF (2003) A tale of two tails: ciliary mechanotransduction in ADPKD. Trends Mol Med 9(6):234–236PubMedCrossRefGoogle Scholar
  5. Cukierman S, Yellen G, Miller M (1985) The K+ channel of sarcoplasmic reticulum. A new look at Cs+ block. Biophys J 48:477–484PubMedCrossRefGoogle Scholar
  6. Dang TX, McCleskey EW (1998) Ion channel selectivity through stepwise changes in binding affinity. J Gen Physiol 111:185–1923PubMedCrossRefGoogle Scholar
  7. Delmas P (2005) Polycystins: polymodal receptor/ion-channel cellular sensors. Pflügers Arch 451(1):264–276PubMedCrossRefGoogle Scholar
  8. Eyring H, Lumry R, Woodbury JW (1949) Some applications of modern rate theory to physiological systems. Rec Chem Prog 10:100–114Google Scholar
  9. French RJ, Worley JF III, Wonderlin WF, Kularatna AS, Krueger BK (1994) Ion permeation, divalent ion block, and chemical modification of single sodium channels. Description by single- and double-occupancy rate-theory models. J Gen Physiol 103(3):447–470PubMedCrossRefGoogle Scholar
  10. Glasstone S, Laidler KJ, Eyring H (1941) The theory of rate processes. McGraw-Hill, New YorkGoogle Scholar
  11. González-Perrett S, Kim K, Ibarra C, Damiano AE, Zotta E, Batelli M, Harris PC, Reisin IL, Arnaout MA, Cantiello HF (2001) Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel. Proc Natl Acad Sci USA 98(3):1182–1187PubMedCrossRefGoogle Scholar
  12. González-Perrett S, Batelli M, Kim K, Essafi M, Timpanaro G, Montalbetti N, Reisin IL M, Arnaout A, Cantiello HF (2002) Voltage dependence and pH regulation of human polycystin-2 mediated cation channel activity. J Biol Chem 277:24959–24966PubMedCrossRefGoogle Scholar
  13. Harris PC, Torres VE (2009) Polycystic kidney disease. Annu Rev Med 60:321–337PubMedCrossRefGoogle Scholar
  14. Hille B (1975) Ionic selectivity, saturation, and block in sodium channels. A four-barrier model. J Gen Physiol 66(5):535–560PubMedCrossRefGoogle Scholar
  15. Hille B (1992) Ionic channels of excitable membranes, 2nd edn. Sinauer, SunderlandGoogle Scholar
  16. Hille B, Schwarz W (1978) Potassium channels as multi-ion single-file pores. J Gen Physiol 72(4):409–442PubMedCrossRefGoogle Scholar
  17. Hladky SB, Haydon DA (1972) Ion transfer across lipid membranes in the presence of gramicidin A. I. Studies of the unit conductance channel. Biochim Biophys Acta 274(2):294–312PubMedCrossRefGoogle Scholar
  18. Hodgkin AL, Keynes RD (1955) The potassium permeability of a giant axon nerve fiber. J Physiol 128:61–88PubMedGoogle Scholar
  19. Ismailov II, Shlyonsky VG, Alvarez O, Benos DJ (1997) Cation permeability of a cloned rat epithelial amiloride-sensitive Na+ channel. J Physiol 504(Pt 2):287–300PubMedCrossRefGoogle Scholar
  20. Keener J, Sneyd J (1992) Mathematical physiology, 2nd edn. Springer, SunderlandGoogle Scholar
  21. Läuger P (1973) Ion transport through pores: a rate-theory analysis. Biochim Biophys Acta 311(3):423–441PubMedCrossRefGoogle Scholar
  22. Li Q, Montalbetti N, Wu Y, Ramos A, Raychowdhury MK, Chen XZ, Cantiello HF (2006) Polycystin-2 cation channel function is under the control of microtubular structures in primary cilia of renal epithelial cells. J Biol Chem 281(49):37566–37575PubMedCrossRefGoogle Scholar
  23. Lide DR (2009–2010) Handbook of chemistry and physics. CRC. 90th edn, pp 5–81 to 5–85Google Scholar
  24. Luo Y, Vassilev PM, Li X, Kawanabe Y, Zhou J (2003) Native polycystin 2 functions as a plasma membrane Ca2+-permeable cation channel in renal epithelia. Mol Cell Biol 23(7):2600–2607PubMedCrossRefGoogle Scholar
  25. Machado-Vieira R, Manji HK, Zarate CA Jr (2009) The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord 11(Suppl 2):92–109PubMedCrossRefGoogle Scholar
  26. Mackey M, McNeel M (1971) The independence principle: a reconsideration. Biophys J 11:675–680PubMedCrossRefGoogle Scholar
  27. Miyoshi K, Kasahara K, Miyazaki I, Asanuma M (2009) Lithium treatment elongates primary cilia in the mouse brain and in cultured cells. Biochem Biophys Res Commun 388(4):757–762PubMedCrossRefGoogle Scholar
  28. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S (1996) PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272:1339–1342PubMedCrossRefGoogle Scholar
  29. Montell C (2001) Physiology, phylogeny, and functions of the TRP superfamily of cation channels. Sci STKE 90:RE1Google Scholar
  30. Nauli SM, Zhou J (2004) Polycystins and mechanosensation in renal and nodal cilia. Bioessays 26(8):844–856PubMedCrossRefGoogle Scholar
  31. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33(2):129–137PubMedCrossRefGoogle Scholar
  32. Nonner W, Chen D, Eisenberg B (1999) Progress and prospects in permeation. J Gen Physiol 113:773–782PubMedCrossRefGoogle Scholar
  33. Raychowdhury MK, McLaughlin M, Ramos AJ, Montalbetti N, Bouley R, Ausiello DA, Cantiello HF (2005) Characterization of single channel currents from primary cilia of renal epithelial cells. J Biol Chem 280(41):34718–34722PubMedCrossRefGoogle Scholar
  34. Schultz SG (1980) Basic principles of membrane transport, 1st edn. Cambridge University Press, New YorkGoogle Scholar
  35. Schumaker MF, MacKinnon R (1990) A simple model for multi-ion permeation. Single-vacancy conduction in a simple pore model. Biophys J 58(4):975–984PubMedCrossRefGoogle Scholar
  36. Segel IH (1975) Enzyme kinetics. Behavior and analysis of rapid equilibrium and steady state enzyme systems, Chap. 7. Wiley-Interscience, New York, pp 391–395Google Scholar
  37. Timmer RT, Sands JM (1999) Lithium intoxication. J Am Soc Nephrol 10:666–674PubMedGoogle Scholar
  38. Urban BW, Hladky SB (1979) Ion transport in the simplest single file pore. Biochim Biophys Acta 554:410–429PubMedCrossRefGoogle Scholar
  39. Urban BW, Hladky SB, Haydon DA (1978) The kinetics of ion movements in the gramicidin channel. Fed Proc 37:2628–2632PubMedGoogle Scholar
  40. Vassilev PM, Guo L, Chen XZ, Segal Y, Peng JB, Basora N, Babakhanlou H, Cruger G, Kanazirska M, Ye CP, Brown EM, Hediger MA, Zhou J (2001) Polycystin-2 is a novel cation channel implicated in defective intracellular Ca2+ homeostasis in polycystic kidney disease. Biochem Biophys Res Commun 282(1):341–350PubMedCrossRefGoogle Scholar
  41. Venkatachalam K, Montell C (2007) TRP channels. Annu Rev Biochem 76:387–417. ReviewGoogle Scholar
  42. Voets T, Nilius B (2003) TRP makes sense. J Membr Biol 192(1): 1–8. ReviewGoogle Scholar
  43. Xu GM, González-Perrett S, Essafi M, Timpanaro GA, Montalbetti N, Arnaout MA, Cantiello HF (2003) Polycystin-1 activates and stabilizes the polycystin-2 channel. J Biol Chem 278(3):1457–1462PubMedCrossRefGoogle Scholar
  44. Zhang P, Luo Y, Chasan B, González-Perrett S, Montalbetti N, Timpanaro GA, Cantero MR, Ramos AJ, Goldmann WH, Zhou J, Cantiello HF (2009) The multimeric structure of polycystin-2 (TRPP2): structural-functional correlates of homo- and hetero-multimers with TRPC1. Hum Mol Genet 18(7):1238–1251PubMedCrossRefGoogle Scholar
  45. Zwolinski B, Eyring H, Reese C (1949) Diffusion and membrane permeability. Colloid Chem 53:1426–1453CrossRefGoogle Scholar

Copyright information

© European Biophysical Societies' Association 2011

Authors and Affiliations

  • María del Rocío Cantero
    • 1
  • Horacio F. Cantiello
    • 1
    • 2
    Email author
  1. 1.Cátedra de Biofísica, Facultad de OdontologíaUBABuenos AiresArgentina
  2. 2.Nephrology Division, Department of MedicineMassachusetts General Hospital East and Harvard Medical SchoolCharlestownUSA

Personalised recommendations