Skip to main content
SpringerLink
Log in

PMCA2w/a Splice Variant: A Key Regulator of Hair Cell Mechano-transduction Machinery

  • Chapter
  • First Online:
Regulation of Ca2+-ATPases,V-ATPases and F-ATPases

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 14))

  • 1020 Accesses

Abstract

Sensory hair cells of the inner ear detect sound stimuli, inertial or gravitational forces. These mechanical inputs cause deflection of the cell stereociliary bundle and activate a small number of cation-selective mechano-transduction (MET) channels that admit K+ and Ca2+ ions into the cytoplasm. Stereociliary Ca2+ levels are homeostatically regulated by an unusual splicing isoform (w/a) of plasma membrane calcium-pump isoform 2 (PMCA2w/a), ablation or missense mutations of which cause deafness and loss of balance in humans and mice. At variance with other PMCA2 isoforms, PMCA2w/a expressed in CHO transfectants increases only marginally its activity in response to a rapid increase of the cytoplasmic free Ca2+ concentration ([Ca2+]c). In this expression system, deafness-related mutations of PMCA2w/a decrease the pump ability to extrude Ca2+ both at steady state and in response to a [Ca2+]c rise. Consistent with these findings, mouse strains in which the pump is genetically ablated or mutated show hearing impairment correlated with defects in homeostatic regulation of stereociliary Ca2+, decreased sensitivity of the MET channels to hair bundle displacement, and morphological abnormalities in the organ of Corti. These results highlight a critical role played by PMCA2w/a in the control of hair cell function and survival and provide mechanistic insight into the etiology of deafness and vestibular disorders.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Carafoli E, Santella L, Branca D et al (2001) Generation, control, and processing of cellular calcium signals. Crit Rev Biochem Mol Biol 36:107–260

    Article  CAS  PubMed  Google Scholar 

  2. Guerini D, Coletto L, Carafoli E (2005) Exporting calcium from cells. Cell Calcium 38:281–289

    Article  CAS  PubMed  Google Scholar 

  3. Crouch JJ, Schulte BA (1996) Identification and cloning of site C splice variants of plasma membrane Ca-ATPase in the gerbil cochlea. Hear Res 101:55–61

    Article  CAS  PubMed  Google Scholar 

  4. Dumont RA, Lins U, Filoteo AG et al (2001) Plasma membrane Ca2 + -ATPase isoform 2a is the PMCA of hair bundles. J Neurosci 21:5066–5078

    CAS  PubMed  Google Scholar 

  5. Chen Q, Mahendrasingam S, Tickle JA et al (2012) The development, distribution and density of the plasma membrane calcium ATPase 2 calcium pump in rat cochlear hair cells. Eur J Neurosci 36:2302–2310

    Article  PubMed  PubMed Central  Google Scholar 

  6. Grati M, Aggarwal N, Strehler EE et al (2006) Molecular determinants for differential membrane trafficking of PMCA1 and PMCA2 in mammalian hair cells. J Cell Sci 119(Pt 14):2995–3007

    Article  CAS  PubMed  Google Scholar 

  7. Grati M, Schneider ME, Lipkow K et al (2006) Rapid turnover of stereocilia membrane proteins: evidence from the trafficking and mobility of plasma membrane Ca(2+)-ATPase 2. J Neurosci 26:6386–6395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Brini M, Coletto L, Pierobon N et al (2003) A comparative functional analysis of plasma membrane Ca2+ pump isoforms in intact cells. J Biol Chem 278:24500–24508

    Article  CAS  PubMed  Google Scholar 

  9. Hilfiker H, Guerini D, Carafoli E (1994) Cloning and expression of isoform 2 of the human plasma membrane Ca2+ ATPase. Functional properties of the enzyme and its splicing products. J Biol Chem 269:26178–26183

    CAS  PubMed  Google Scholar 

  10. Krebs J (2015) The plethora of PMCA isoforms: alternative splicing and differential expression. Biochim Biophys Acta 1853:2018. doi:10.1016/j.bbamcr.2014.12.020, pii: S0167-4889(14)00448-0

    Article  CAS  PubMed  Google Scholar 

  11. Zacharias DA, Strehler EE (1996) Change in plasma membrane Ca2(+)-ATPase splice-variant expression in response to a rise in intracellular Ca2+. Curr Biol 6:1642–1652

    Article  CAS  PubMed  Google Scholar 

  12. Stamm S (2008) Regulation of alternative splicing by reversible protein phosphorylation. J Biol Chem 283:1223–1227

    Article  CAS  PubMed  Google Scholar 

  13. Brodin P, Falchetto R, Vorherr T et al (1992) Identification of two domains which mediate the binding of activating phospholipids to the plasma-membrane Ca2+ pump. Eur J Biochem 204:939–946

    Article  CAS  PubMed  Google Scholar 

  14. Elwess NL, Filoteo AG, Enyedi A et al (1997) Plasma membrane Ca2+ pump isoforms 2a and 2b are unusually responsive to calmodulin and Ca2+. J Biol Chem 272:17981–17986

    Article  CAS  PubMed  Google Scholar 

  15. Niggli V, Adunyah ES, Penniston JT et al (1981) Purified (Ca2 + -Mg2+)-ATPase of the erythrocyte membrane. Reconstitution and effect of calmodulin and phospholipids. J Biol Chem 256:395–401

    CAS  PubMed  Google Scholar 

  16. Lim DJ (1986) Functional structure of the organ of Corti: a review. Hear Res 22:117–146

    Article  CAS  PubMed  Google Scholar 

  17. Hill JK, Williams DE, LeMasurier M et al (2006) Splice-site A choice targets plasma-membrane Ca2 + -ATPase isoform 2 to hair bundles. J Neurosci 26:6172–6180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fettiplace R, Kim KX (2014) The physiology of mechanoelectrical transduction channels in hearing. Physiol Rev 94:951–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Carafoli E (2011) The plasma membrane calcium pump in the hearing process: physiology and pathology. Sci China Life Sci 54:686–690

    Article  CAS  PubMed  Google Scholar 

  20. Corey DP, Sotomayor M (2004) Hearing: tightrope act. Nature 428:901–903

    Article  CAS  PubMed  Google Scholar 

  21. Anniko M, Wroblewski R (1986) Ionic environment of cochlear hair cells. Hear Res 22:279–293

    Article  CAS  PubMed  Google Scholar 

  22. Corey DP, Hudspeth AJ (1979) Ionic basis of the receptor potential in a vertebrate hair cell. Nature 281:675–677

    Article  CAS  PubMed  Google Scholar 

  23. Ohmori H (1985) Mechano-electrical transduction currents in isolated vestibular hair cells of the chick. J Physiol 359:189–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lumpkin EA, Marquis RE, Hudspeth AJ (1997) The selectivity of the hair cell’s mechanoelectrical-transduction channel promotes Ca2+ flux at low Ca2+ concentrations. Proc Natl Acad Sci U S A 94:10997–11002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Denk W, Holt JR, Shepherd GM et al (1995) Calcium imaging of single stereocilia in hair cells: localization of transduction channels at both ends of tip links. Neuron 15:1311–1321

    Article  CAS  PubMed  Google Scholar 

  26. Jorgensen F, Kroese AB (1995) Ca selectivity of the transduction channels in the hair cells of the frog sacculus. Acta Physiol Scand 155:363–376

    Article  CAS  PubMed  Google Scholar 

  27. Bosher SK, Warren RL (1978) Very low calcium content of cochlear endolymph, an extracellular fluid. Nature 273:377–378

    Article  CAS  PubMed  Google Scholar 

  28. Wood JD, Muchinsky SJ, Filoteo AG et al (2004) Low endolymph calcium concentrations in deafwaddler2J mice suggest that PMCA2 contributes to endolymph calcium maintenance. J Assoc Res Otolaryngol 5:99–110

    Article  PubMed  PubMed Central  Google Scholar 

  29. Corey DP, Hudspeth AJ (1983) Kinetics of the receptor current in bullfrog saccular hair cells. J Neurosci 3:962–976

    CAS  PubMed  Google Scholar 

  30. Marquis RE, Hudspeth AJ (1997) Effects of extracellular Ca2+ concentration on hair-bundle stiffness and gating-spring integrity in hair cells. Proc Natl Acad Sci U S A 94:11923–11928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hackney CM, Mahendrasingam S, Penn A et al (2005) The concentrations of calcium buffering proteins in mammalian cochlear hair cells. J Neurosci 25:7867–7875

    Article  CAS  PubMed  Google Scholar 

  32. Ricci AJ, Wu YC, Fettiplace R (1998) The endogenous calcium buffer and the time course of transducer adaptation in auditory hair cells. J Neurosci 18:8261–8277

    CAS  PubMed  Google Scholar 

  33. Lumpkin EA, Hudspeth AJ (1998) Regulation of free Ca2+ concentration in hair-cell stereocilia. J Neurosci 18:6300–6318

    CAS  PubMed  Google Scholar 

  34. Yamoah EN, Lumpkin EA, Dumont RA et al (1998) Plasma membrane Ca2 + -ATPase extrudes Ca2+ from hair cell stereocilia. J Neurosci 18:610–624

    CAS  PubMed  Google Scholar 

  35. Ricci AJ, Fettiplace R (1998) Calcium permeation of the turtle hair cell mechanotransducer channel and its relation to the composition of endolymph. J Physiol 506(Pt 1):159–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Crouch JJ, Schulte BA (1995) Expression of plasma membrane Ca-ATPase in the adult and developing gerbil cochlea. Hear Res 92:112–119

    Article  CAS  PubMed  Google Scholar 

  37. Wu YC, Tucker T, Fettiplace R (1996) A theoretical study of calcium microdomains in turtle hair cells. Biophys J 71:2256–2275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shah DM, Freeman DM, Weiss TF (1995) The osmotic response of the isolated, unfixed mouse tectorial membrane to isosmotic solutions: effect of Na+, K+, and Ca2+ concentration. Hear Res 87:187–207

    Article  CAS  PubMed  Google Scholar 

  39. Kozel PJ, Friedman RA, Erway LC et al (1998) Balance and hearing deficits in mice with a null mutation in the gene encoding plasma membrane Ca2 + -ATPase isoform 2. J Biol Chem 273:18693–18696

    Article  CAS  PubMed  Google Scholar 

  40. Street VA, McKee-Johnson JW, Fonseca RC et al (1998) Mutations in a plasma membrane Ca2 + -ATPase gene cause deafness in deafwaddler mice. Nat Genet 19:390–394

    Article  CAS  PubMed  Google Scholar 

  41. Takahashi K, Kitamura K (1999) A point mutation in a plasma membrane Ca(2+)-ATPase gene causes deafness in Wriggle Mouse Sagami. Biochem Biophys Res Commun 261:773–778

    Article  CAS  PubMed  Google Scholar 

  42. McCullough BJ, Tempel BL (2004) Haplo-insufficiency revealed in deafwaddler mice when tested for hearing loss and ataxia. Hear Res 195:90–102

    Article  CAS  PubMed  Google Scholar 

  43. Tsai YS, Pendse A, Moy SS et al (2006) A de novo deafwaddler mutation of Pmca2 arising in ES cells and hitchhiking with a targeted modification of the Pparg gene. Mamm Genome 17:716–722

    Article  CAS  PubMed  Google Scholar 

  44. Spiden SL, Bortolozzi M, Di Leva F et al (2008) The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss. PLoS Genet 4:e1000238

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bortolozzi M, Brini M, Parkinson N et al (2010) The novel PMCA2 pump mutation Tommy impairs cytosolic calcium clearance in hair cells and links to deafness in mice. J Biol Chem 285:37693–37703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schultz JM, Yang Y, Caride AJ et al (2005) Modification of human hearing loss by plasma-membrane calcium pump PMCA2. N Engl J Med 352:1557–1564

    Article  CAS  PubMed  Google Scholar 

  47. Ficarella R, Di Leva F, Bortolozzi M et al (2007) A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic deafness. Proc Natl Acad Sci U S A 104:1516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lane PW (1987) New mutants and linkages: deafwaddler (dfw). Mouse News Lett 77:129

    Google Scholar 

  49. Brini M, Marsault R, Bastianutto C et al (1995) Transfected aequorin in the measurement of cytosolic Ca2+ concentration ([Ca2+]c). A critical evaluation. J Biol Chem 270:9896–9903

    Article  CAS  PubMed  Google Scholar 

  50. Beurg M, Nam JH, Chen Q et al (2010) Calcium balance and mechanotransduction in rat cochlear hair cells. J Neurophysiol 104:18–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fettiplace R, Ricci AJ (2006) Mechanoelectrical transduction in auditory hair cells. In: Eatock RA, Fay RR, Popper AN (eds) Vertebrate hair cells. Springer Science Inc., New York, NY, pp 154–203

    Chapter  Google Scholar 

  52. Beurg M, Evans MG, Hackney CM, Fettiplace R (2006) A Large-Conductance Calcium-Selective Mechanotransducer Channel in Mammalian Cochlear Hair Cells. J Neurosci 26:10992–11000

    Article  CAS  PubMed  Google Scholar 

  53. Tucker T, Fettiplace R (1995) Confocal imaging of calcium microdomains and calcium extrusion in turtle hair cells. Neuron 15:1323–1335

    Article  CAS  PubMed  Google Scholar 

  54. Wu YC, Ricci AJ, Fettiplace R (1999) Two components of transducer adaptation in auditory hair cells. J Neurophysiol 82:2171–2181

    CAS  PubMed  Google Scholar 

  55. Scimemi P, Santarelli R, Selmo A et al (2014) Auditory brainstem responses to clicks and tone bursts in C57 BL/6J mice. Acta Otorhinolaryngol Ital 34:264–271

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Watson CJ, Tempel BL (2013) A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers. Hear Res 304:41–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Noben-Trauth K, Zheng QY, Johnson KR (2003) Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss. Nat Genet 35:21–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Corns LF, Johnson SL, Kros CJ et al (2014) Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells. Proc Natl Acad Sci U S A 111:14918–14923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhao Y, Yamoah EN, Gillespie PG (1996) Regeneration of broken tip links and restoration of mechanical transduction in hair cells. Proc Natl Acad Sci U S A 93:15469–15474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Walker RG, Hudspeth AJ, Gillespie PG (1993) Calmodulin and calmodulin-binding proteins in hair bundles. Proc Natl Acad Sci U S A 90:2807–2811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Assad JA, Shepherd GM, Corey DP (1991) Tip-link integrity and mechanical transduction in vertebrate hair cells. Neuron 7:985–994

    Article  CAS  PubMed  Google Scholar 

  62. Assad JA, Hacohen N, Corey DP (1989) Voltage dependence of adaptation and active bundle movement in bullfrog saccular hair cells. Proc Natl Acad Sci U S A 86:2918–2922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Eatock RA, Corey DP, Hudspeth AJ (1987) Adaptation of mechanoelectrical transduction in hair cells of the bullfrog’s sacculus. J Neurosci 7:2821–2836

    CAS  PubMed  Google Scholar 

  64. Kazmierczak P, Sakaguchi H, Tokita J et al (2007) Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature 449:87–91

    Article  CAS  PubMed  Google Scholar 

  65. Lefevre G, Michel V, Weil D et al (2008) A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth. Development 135:1427–1437

    Article  CAS  PubMed  Google Scholar 

  66. Maeda R, Kindt KS, Mo W et al (2014) Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2. Proc Natl Acad Sci U S A 111:12907–12912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The work summarized here was carried out by the authors’ team in collaboration with research teams led by Ernesto Carafoli, Marisa Brini, Paolo Gasparini, Karen Steel, Steve Brown, and the late Edoardo Arslan. For grant support, see Refs. [44, 45, 47].

Author information

Authors and Affiliations

  1. Department of Physics and Astronomy “G. Galilei”, University of Padua, Via Marzolo 8, 35131, Padua, Italy

    Mario Bortolozzi & Fabio Mammano

  2. Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129, Padua, Italy

    Mario Bortolozzi & Fabio Mammano

  3. CNR Institute of Cell Biology and Neurobiology, Via E. Ramarini, 32, 00015, Monterotondo, Scalo Roma, Italy

    Fabio Mammano

Authors
  1. Mario Bortolozzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabio Mammano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fabio Mammano .

Editor information

Editors and Affiliations

  1. Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. University of Manitoba, Institute of Cardiovascular Science St. Boniface Hospital Research, Winnipeg, Manitoba, Canada

    Naranjan S Dhalla

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Bortolozzi, M., Mammano, F. (2016). PMCA2w/a Splice Variant: A Key Regulator of Hair Cell Mechano-transduction Machinery. In: Chakraborti, S., Dhalla, N. (eds) Regulation of Ca2+-ATPases,V-ATPases and F-ATPases. Advances in Biochemistry in Health and Disease, vol 14. Springer, Cham. https://doi.org/10.1007/978-3-319-24780-9_3

Download citation

Publish with us

Policies and ethics

Search

Navigation