Differential distribution of adenosine receptors in rat cochlea


Adenosine is a constitutive cell metabolite that can be released from cells via specific bi-directional transporters and is an end-point for nucleotide hydrolysis. In the extracellular space, adenosine becomes a signalling molecule for P1 (adenosine) receptors that modulate physiological responses in a wide range of mammalian tissues. Whereas adenosine signalling has been implicated in the regulation of cochlear blood flow and in cochlear protection from oxidative damage, the potential roles for adenosine signalling in the modulation of sound transduction and auditory neurotransmission have not been established. We have characterised the expression and distribution of adenosine receptors in the rat cochlea. mRNA transcripts for all four subtypes of adenosine receptors (A1, A2A, A2B and A3) were detected in dissected cochlear tissue by using reverse transcription/polymerase chain reaction analysis. The protein distribution for the A1, A2A and A3 receptor subtypes was identified by immunoperoxidase histochemistry and confocal immunofluorescence labelling. These receptors were differentially expressed in the organ of Corti, spiral ganglion neurones, lateral wall tissues and cochlear blood vessels. The distribution of adenosine receptors in sensory and neural tissues and in the vasculature coincided with other elements of purinergic signalling (P2X and P2Y receptors, ectonucleotidases), consistent with the integrative regulation of many physiological processes in the cochlea by extracellular nucleotides and nucleosides. Our study provides a framework for further investigation of adenosine signalling in the inner ear, including putative roles in oxidative stress responses.

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  1. Alloisio S, Cugnoli C, Ferroni S, Nobile M (2004) Differential modulation of ATP-induced calcium signalling by A1 and A2 adenosine receptors in cultured cortical astrocytes. Br J Pharmacol 141:935–942

  2. Aubert A, Norris CH, Guth PS (1994) Influence of ATP and ATP agonists on the physiology of the isolated semicircular canal of the frog (Rana pipiens). Neurosci 62:963–974

  3. Bobbin RP (2001) ATP-induced movement of the stalks of isolated cochlear Deiters’ cells. Neuroreport 12:2923–2926

  4. Bobbin RP, Bledsoe SC Jr (2005) Asphyxia and depolarization increase adenosine levels in perilymph. Hear Res 205:110–114

  5. Brand A, Vissiennon Z, Eschke D, Nieber K (2001) Adenosine A1 and A3 receptors mediate inhibition of synaptic transmission in rat cortical neurons. Neuropharmacology 40:85–95

  6. Bryant GM, Barron SE, Norris CH, Guth PS (1987) Adenosine is a modulator of hair cell-afferent neurotransmission. Hear Res 30:231–237

  7. Bucheimer RE, Linden J (2004) Purinergic regulation of epithelial transport. J Physiol (Lond) 555:311–321

  8. Chen C, Bobbin RP (1998) P2X receptors in cochlear Deiters’ cells. Br J Pharmacol 124:337–344

  9. Chen JF, Huang Z, Ma J, Zhu J, Moratalla R, Standaert D, Moskowitz MA, Fink JS, Schwarzschild MA (1999) A(2A) adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J Neurosci 19:9192–9200

  10. Coney AM, Marshall JM (1998) Role of adenosine and its receptors in the vasodilatation induced in the cerebral cortex of the rat by systemic hypoxia. J Physiol (Lond) 509:507–518

  11. Costenla AR, Lopes LV, Mendonca A de, Ribeiro JA (2001) A functional role for adenosine A3 receptors: modulation of synaptic plasticity in the rat hippocampus. Neurosci Lett 302:53–57

  12. Crouch JJ, Sakaguchi N, Lytle C, Schulte BA (1997) Immunohistochemical localization of the Na-K-Cl co-transporter (NKCC1) in the gerbil inner ear. J Histochem Cytochem 45:773–778

  13. Cunha RA (2001) Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochem Int 38:107–125

  14. Cunha RA (2005) Neuroprotection by adenosine in the brain: from A1 receptor activation to A2A receptor blockade. Purinergic Signalling 1:111–134

  15. Diniz C, Leal S, Goncalves J (2003) Regional differences in the adenosine A(2) receptor-mediated modulation of contractions in rat vas deferens. Eur J Pharmacol 460:191–199

  16. Diniz C, Fresco P, Leal S, Goncalves J (2004) Adenosine receptors involved in modulation of noradrenaline release in isolated rat tail artery. Eur J Pharmacol 504:17–25

  17. Dulon D, Mollard P, Aran JM (1991) Extracellular ATP elevates cytosolic Ca2+ in cochlear IHC. Neuroreport 2:69–72

  18. Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55

  19. Ford MS, Maggirwar SB, Rybak LP, Whitworth C, Ramkumar V (1997) Expression and function of adenosine receptors in the chinchilla cochlea. Hear Res 105:130–140

  20. Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552

  21. Fredholm BB, Chen JF, Cunha RA, Svenningsson P, Vaugeois JM (2005) Adenosine and brain function. Int Rev Neurobiol 63:191–270

  22. Hight NG, Sandra LM, Henderson D, Robert F, Burkard F, Nicotera T (2003) Noise-induced hearing loss in chinchillas pre-treated with glutathione monoethylester and R-PIA. Hear Res 179:21–32

  23. Housley GD (2001) Nucleoside and nucleotide transmission in sensory systems. In: Abbracchio M (ed) Purinergic and pyrimidinergic signalling. I. Molecular, nervous and urogenitary system function. Springer, Heidelberg, pp 339–369

  24. Housley GD, Kanjhan R, Raybould NP, Greenwood D, Salih SG, Jarlebark L, Burton LD, Setz VC, Cannell MB, Soeller C, Christie DL, Usami S, Matsubara A, Yoshie H, Ryan AF, Thorne PR (1999) Expression of the P2X(2) receptor subunit of the ATP-gated ion channel in the cochlea: implications for sound transduction and auditory neurotransmission. J Neurosci 19:8377–8388

  25. Housley GD, Jagger DJ, Greenwood D, Raybould NP, Salih SG, Jarlebark LE, Vlajkovic SM, Kanjhan R, Nikolic P, Muñoz DJ, Thorne PR (2002) Purinergic regulation of sound transduction and auditory neurotransmission. Audiol Neurootol 7:55–61

  26. Housley GD, Huang LC, Barclay M, Greenwood D, Raybould NP, Yang L, Muñoz DJB, Vlajkovic SM, Thorne PR (2004) Contribution of P2X and P2Y receptor signalling in the cochlear partition to the regulation of sound transduction. Proc 4th Int Symposium of Nucleosides and Nucleotides, Chapel Hill, N.C., USA, p 87

  27. Housley GD, Marcotti W, Navaratnam D, Yamoah EN (2006) Hair cells—beyond the transducer. J Membr Biol 209:89–118

  28. Hu BH, Zheng XY, McFadden SL, Kopke RD, Henderson D (1997) R-phenylisopropyladenosine attenuates noise-induced hearing loss in the chinchilla. Hear Res 113:198–206

  29. Lasley RD, Narayan P, Uittenbogaard A, Smart EJ (2000) Activated cardiac adenosine A1 receptors translocate out of caveolae. J Biol Chem 275:4417–4421

  30. Li H, Henry JL (1998) Adenosine A2 receptor mediation of pre- and postsynaptic excitatory effects of adenosine in rat hippocampus in vitro. Eur J Pharmacol 347:173–182

  31. Lopes LV, Rebola N, Pinheiro PC, Richardson PJ, Oliveira CR, Cunha RA (2003) Adenosine A3 receptors are located in neurons of the rat hippocampus. Neuroreport 14:1645–1648

  32. Miller JM, Ren TY, Nuttall AL (1995) Studies of inner ear blood flow in animals and human beings. Otolaryngol Head Neck Surg 112:101–113

  33. Muñoz DJB, Thorne PR, Housley GD, Billett TE, Battersby JM (1995) Extracellular adenosine 5′-triphosphate (ATP) in the endolymphatic compartment influences cochlear function. Hear Res 90:106–118

  34. Muñoz DJB, McFie C, Thorne PR (1999) Modulation of cochlear blood flow by extracellular purines. Hear Res 127:55–61

  35. Nario K, Kitano I, Mori N, Matsunaga T (1994) The effect of adenosine on cochlear potentials in the guinea pig. Eur Arch Otorhinolaryngol 251:428–433

  36. Newby AC (1991) Adenosine: origin and clinical roles. Adv Exp Med Biol 309A:265–270

  37. Nie Z, Mei Y, Malek RL, Marcuzzi A, Lee NH, Ramkumar V (1999) A role of p75 in NGF-mediated down-regulation of the A(2A) adenosine receptors in PC12 cells. Mol Pharmacol 56:947–954

  38. Ponzio TA, Hatton GI (2005) Adenosine postsynaptically modulates supraoptic neuronal excitability. J Neurophysiol 93:535–547

  39. Ramkumar V, Whitworth CA, Pingle SC, Hughes LF, Rybak LP (2004) Noise induces A1 adenosine receptor expression in the chinchilla cochlea. Hear Res 188:47–56

  40. Ribeiro JA, Sebastiao AM, Mendonca A de (2003) Participation of adenosine receptors in neuroprotection. Drug News Perspect 16:80–86

  41. Seidman MD, Quirk WS, Shirwany NA (1999) Mechanisms of alterations in the microcirculation of the cochlea. Ann NY Acad Sci 884:226–232

  42. Smith JA, Sivaprasadarao A, Munsey TS, Bowmer CJ, Yates MS (2001) Immunolocalisation of adenosine A(1) receptors in the rat kidney. Biochem Pharmacol 61:237–244

  43. Thorne PR, Muñoz DJ, Nikolic P, Mander L, Jagger DJ, Greenwood D, Vlajkovic S, Housley GD (2002) Potential role of purinergic signalling in cochlear pathology. Audiol Neurootol 7:180–184

  44. Thorne PR, Muñoz DJ, Housley GD (2004) Purinergic modulation of cochlear partition resistance and its effect on the endocochlear potential in the guinea pig. J Assoc Res Otolaryngol 5:58–65

  45. Trincavelli ML, Tuscano D, Cecchetti P, Falleni A, Benzi L, Klotz KN, Gremigni V, Cattabeni F, Lucacchini A, Martini C (2000) Agonist-induced internalization and recycling of the human A(3) adenosine receptors: role in receptor desensitization and resensitization. J Neurochem 75:1493–1501

  46. Tsutsui S, Schnermann J, Noorbakhsh F, Henry S, Yong VW, Winston BW, Warren K, Power C (2004) A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis. J Neurosci 24:1521–1529

  47. Van den Abbeele T, Tran Ba Huy P, Teulon J (1996) Modulation by purines of calcium-activated non-selective cation channels in the OHC of the guinea-pig cochlea. J Physiol (Lond) 494:77–89

  48. Vlajkovic SM, Thorne PR, Housley GD, Muñoz DJ, Kendrick IS (1998) Ecto-nucleotidases terminate purinergic signalling in the cochlear endolymphatic compartment. Neuroreport 9:1559–1565

  49. Vlajkovic SM, Housley GD, Greenwood D, Thorne PR (1999) Evidence for alternative splicing of ecto-ATPase associated with termination of purinergic transmission. Mol Brain Res 73:85–92

  50. Vlajkovic SM, Thorne PR, Sevigny J, Housley GD (2002) Distribution of ectonucleoside triphosphate diphosphohydrolases 1 and 2 in rat cochlea. Hear Res 170:127–138

  51. Vlajkovic SM, Vinayagamoorthy A, Thorne PR, Robson SC, Wang CJ, Housley GD (2006) Noise-induced up-regulation of NTPDase3 expression in the rat cochlea: implications for auditory transmission and cochlear protection. Brain Res 1104:55–63

  52. Wangemann P (2002) K+ cycling and the endocochlear potential. Hear Res 165:1–9

  53. Yip L, Kwok YN (2004) Role of adenosine A2A receptor in the regulation of gastric somatostatin release. J Pharmacol Exp Ther 309:804–815

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Correspondence to Srdjan M. Vlajkovic.

Additional information

The study was supported by the RNID (UK), Deafness Research Foundation (NZ), Auckland Medical Research Foundation and Health Research Council (NZ).

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Vlajkovic, S.M., Abi, S., Wang, C.J.H. et al. Differential distribution of adenosine receptors in rat cochlea. Cell Tissue Res 328, 461–471 (2007) doi:10.1007/s00441-006-0374-2

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  • Cochlea
  • Adenosine
  • Adenosine receptors
  • P1 receptors
  • Purinergic signalling
  • Rat (Wistar, male)