Cellular Mechanisms of Neuronal Cl Homeostasis and its Modulation by Neuronal Injury

Chapter

Abstract

The function of the brain depends on the fine balance between inhibition and excitation of neurons. The polarity and amplitude of an inhibitory synaptic response depends on both the relative permeability of the receptor-channels involved, and also on the driving force for the permeant ions which is established by an array of active membrane transport proteins. At inhibitory synapses, the cation chloride co-transporters, including NKCC1 and KCC2, are particularly important in determining intracellular Cl concentrations and the efficacy of inhibitory synaptic responses. Recent experiments have shown that the expression and activity of these transporters can change, not only over development, but also in response to neuronal injury. In this article, we review the basic biophysical aspects and role of different transporters in neuronal Cl homeostasis and how the expression and function of these transporters, particularly KCC2, changes during development and in response to a wide range of models of neuronal injury. We also review recent data regarding the cellular and molecular mechanisms by which injury induced changes in KCC2 function may occur. Our review hopes to highlight the need for further investigation of these processes, to enable a greater understanding of developmental and pathological plasticity at inhibitory synapses, and to enable the potential development of novel therapeutic strategies to treat neuronal dysfunction.

References

  1. Adragna NC, Fulvio MD, Lauf PK (2004) Regulation of K-Cl cotransport: from function to genes. J Membr Biol 201:109–137.CrossRefPubMedGoogle Scholar
  2. Ben-Ari Y (2002) Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci 3:728–739.CrossRefPubMedGoogle Scholar
  3. Blaesse P, Guillemin I, Schindler J, Schweizer M, Delpire E, Khiroug L, Friauf E, Nothwang HG (2006) Oligomerization of KCC2 correlates with development of inhibitory neurotransmission. J Neurosci 26:10407–10419.CrossRefPubMedGoogle Scholar
  4. Blaesse P, Airaksinen MS, Rivera C, Kaila K (2009) Cation-chloride cotransporters and neuronal function. Neuron 61:820–838.CrossRefPubMedGoogle Scholar
  5. Barolet AW, Morris ME (1991) Changes in extracellular K+ evoked by GABA, THIP and baclofen in the guinea-pig hippocampal slice. Exp Brain Res 84:591–598.CrossRefPubMedGoogle Scholar
  6. Carland JE, Moorhouse AJ, Barry PH, Johnston GA, Chebib M (2004) Charged residues at the 2′ position of human GABAC rho 1 receptors invert ion selectivity and influence open state probability. J Biol Chem 279:54153–54160.CrossRefPubMedGoogle Scholar
  7. Carland JE, Cooper MA, Sugiharto S, Jeong HJ, Lewis TM, Barry PH, Peters JA, Lambert JJ, Moorhouse AJ (2009) Characterization of the effects of charged residues in the intracellular loop on ion permeation in alpha1 glycine receptor channels. J Biol Chem 284:2023–2030.CrossRefPubMedGoogle Scholar
  8. Clayton GH, Owens GC, Wolff JS, Smith RL (1998) Ontogeny of cation-Cl- cotransporter expression in rat neocortex. Dev Brain Res 109:281–292.CrossRefGoogle Scholar
  9. Coull JA, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, De Koninck P, De Koninck Y (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424:938–942.CrossRefPubMedGoogle Scholar
  10. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021.CrossRefPubMedGoogle Scholar
  11. Farrant M, Kaila K (2007) The cellular, molecular and ionic basis of GABA(A) receptor signalling. Prog Brain Res 160:59–87.CrossRefPubMedGoogle Scholar
  12. Galeffi F, Sah R, Pond BB, George A, Schwartz-Bloom RD (2004) Changes in intracellular chloride after oxygen-glucose deprivation of the adult hippocampal slice: effect of diazepam. J Neurosci 24:4478–4488.CrossRefPubMedGoogle Scholar
  13. Gamba G (2005) Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev 85:423–493.CrossRefPubMedGoogle Scholar
  14. Garbarini N, Delpire E (2008) The RCC1 domain of protein associated with Myc (PAM) interacts with and regulates KCC2. Cell Physiol Biochem 22:31–44.CrossRefPubMedGoogle Scholar
  15. Gulácsi A, Lee CR, Sík A, Viitanen T, Kaila K, Tepper JM, Freund TF (2003) Cell type-specific differences in chloride-regulatory mechanisms and GABA(A) receptor-mediated inhibition in rat substantia nigra. J Neurosci 23:8237–8246.PubMedGoogle Scholar
  16. Hebert SC, Mount DB, Gamba G (2004) Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Pflugers Arch 447:580–593.CrossRefPubMedGoogle Scholar
  17. Hershfinkel M, Kandler K, Knoch ME, Dagan-Rabin M, Aras MA, Abramovitch-Dahan C, Sekler I, Aizenman E (2009) Intracellular zinc inhibits KCC2 transporter activity. Nat Neurosci 12:725–727.CrossRefPubMedGoogle Scholar
  18. Huberfeld G, Wittner L, Clemenceau S, Baulac M, Kaila K, Miles R, Rivera C (2007) Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy. J Neurosci 27:9866–9873.CrossRefPubMedGoogle Scholar
  19. Inagaki C, Hattori N, Kitagawa K, Zeng XT, Yagyu K (2001) Cl()-ATPase in rat brain and kidney. J Exp Zool 289:224–231.CrossRefPubMedGoogle Scholar
  20. Inoue K, Yamada J, Ueno S, Fukuda A (2006) Brain-type creatine kinase activates neuron-specific K+-Cl co-transporter KCC2. J Neurochem 96:598–608.CrossRefPubMedGoogle Scholar
  21. Jang IS, Jeong HJ, Akaike N (2001) Contribution of the Na-K-Cl cotransporter on GABA(A) receptor-mediated presynaptic depolarization in excitatory nerve terminals. J Neurosci 21:5962–5972.PubMedGoogle Scholar
  22. Jang IS, Nakamura M, Ito Y, Akaike N (2006) Presynaptic GABAA receptors facilitate spontaneous glutamate release from presynaptic terminals on mechanically dissociated rat CA3 pyramidal neurons. Neuroscience 138:25–35.CrossRefPubMedGoogle Scholar
  23. Kaila K (1994) Ionic basis of GABAA receptor channel function in the nervous system. Prog Neurobiol 42:489–537.CrossRefPubMedGoogle Scholar
  24. Kakazu Y, Akaike N, Komiyama S, Nabekura J (1999) Regulation of intracellular chloride by cotransporters in developing lateral superior olive neurons. J Neurosci 19:2843–2851.PubMedGoogle Scholar
  25. Kakazu Y, Uchida S, Nakagawa T, Akaike N, Nabekura J (2000) Reversibility and cation selectivity of the K(+)-Cl(−) cotransport in rat central neurons. J Neurophysiol 84:281–288.PubMedGoogle Scholar
  26. Kahle KT, Staley KJ, Nahed BV, Gamba G, Hebert SC, Lifton RP, Mount DB (2008) Roles of the cation-chloride cotransporters in neurological disease. Nat Clin Pract Neurol 4:490–503.CrossRefPubMedGoogle Scholar
  27. Khirug S, Huttu K, Ludwig A, Smirnov S, Voipio J, Rivera C, Kaila K, Khiroug L (2005) Distinct properties of functional KCC2 expression in immature mouse hippocampal neurons in culture and in acute slices. Eur J Neurosci 21:899–904.CrossRefPubMedGoogle Scholar
  28. Lee HH, Walker JA, Williams JR, Goodier RJ, Payne JA, Moss SJ (2007) Direct protein kinase C-dependent phosphorylation regulates the cell surface stability and activity of the potassium chloride cotransporter KCC2. J Biol Chem 282:29777–29784.CrossRefPubMedGoogle Scholar
  29. Li H, Khirug S, Cai C, Ludwig A, Blaesse P, Kolikova J, Afzalov R, Coleman SK, Lauri S, Airaksinen MS, Keinänen K, Khiroug L, Saarma M, Kaila K, Rivera C (2007) KCC2 interacts with the dendritic cytoskeleton to promote spine development. Neuron 56:1019–1033.CrossRefPubMedGoogle Scholar
  30. Nabekura J, Ueno T, Okabe A, Furuta A, Iwaki T, Shimizu-Okabe C, Fukuda A, Akaike N (2002) Reduction of KCC2 expression and GABAA receptor-mediated excitation after in vivo axonal injury. J Neurosci 22:4412–4417.PubMedGoogle Scholar
  31. Nickell WT, Kleene NK, Kleene SJ (2007) Mechanisms of neuronal chloride accumulation in intact mouse olfactory epithelium. J Physiol 583:1005–1020.CrossRefPubMedGoogle Scholar
  32. Okabe A, Ohno K, Toyoda H, Yokokura M, Sato K, Fukuda A (2002) Amygdala kindling induces upregulation of mRNA for NKCC1, a Na(+), K(+)-2Cl(−) cotransporter, in the rat piriform cortex. Neurosci Res 44:225–229.CrossRefPubMedGoogle Scholar
  33. Papp E, Rivera C, Kaila K, Freund TF (2008) Relationship between neuronal vulnerability and potassium-chloride cotransporter 2 immunoreactivity in hippocampus following transient forebrain ischemia. Neuroscience 154:677–689.CrossRefPubMedGoogle Scholar
  34. Payne JA, Rivera C, Voipio J, Kaika K (2003) Cation-chloride co-transporters in neuronal communication, development and trauma. Trends Neurosci 26:199–206.CrossRefPubMedGoogle Scholar
  35. Pond BB, Berglund K, Kuner T, Feng G, Augustine GJ, Schwartz-Bloom RD (2006) The chloride transporter Na(+)-K(+)-Cl cotransporter isoform-1 contributes to intracellular chloride increases after in vitro ischemia. J Neurosci 26:1396–1406.CrossRefPubMedGoogle Scholar
  36. Represa A, Ben-Ari Y (2005) Trophic actions of GABA on neuronal development. Trends Neurosci 28:278–283.CrossRefPubMedGoogle Scholar
  37. Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K (1999) The K+/Cl co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397:251–255.CrossRefPubMedGoogle Scholar
  38. Rivera C, Li H, Thomas-Crusells J, Lahtinen H, Viitanen T, Nanobashvili A, Kokaia Z, Airaksinen MS, Voipio J, Kaila K, Saarma M (2002) BDNF-induced TrkB activation down-regulates the K+-Cl cotransporter KCC2 and impairs neuronal Cl- extrusion. J Cell Biol 159:747–752.CrossRefPubMedGoogle Scholar
  39. Rivera C, Voipio J, Thomas-Crusells J, Li H, Emri Z, Sipila S, Payne JA, Minichiello L, Saarma M, Kaila K (2004) Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2. J Neurosci 24:4683–4691.CrossRefPubMedGoogle Scholar
  40. Rivera C, Voipio J, Kaila K (2005) Two developmental switches in GABAergic signalling: the K+-Cl cotransporter KCC2 and carbonic anhydrase CAVII. J Physiol 562:27–36.CrossRefPubMedGoogle Scholar
  41. Rocha-González HI, Mao S, Alvarez-Leefmans FJ (2008) Na+,K+,2Cl cotransport and intracellular chloride regulation in rat primary sensory neurons: thermodynamic and kinetic aspects. J Neurophysiol 100:169–184.CrossRefPubMedGoogle Scholar
  42. Shulga A, Thomas-Crusells J, Sigl T, Blaesse A, Mestres P, Meyer M, Yan Q, Kaila K, Saarma M, Rivera C, Giehl KM (2008) Posttraumatic GABA(A)-mediated [Ca2+]i increase is essential for the induction of brain-derived neurotrophic factor-dependent survival of mature central neurons. J Neurosci 28:6996–7005.CrossRefPubMedGoogle Scholar
  43. Song L, Mercado A, Vázquez N, Xie Q, Desai R, George AL Jr, Gamba G, Mount DB (2002) Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporter. Mol Brain Res 103:91–105.CrossRefPubMedGoogle Scholar
  44. Sugiharto S, Lewis TM, Moorhouse AJ, Schofield PR, Barry PH (2008) Anion-cation permeability correlates with hydrated counterion size in glycine receptor channels. Biophys J 95:4698–4715.CrossRefPubMedGoogle Scholar
  45. Tornberg J, Voikar V, Savilahti H, Rauvala H, Airaksinen MS (2005) Behavioural phenotypes of hypomorphic KCC2-deficient mice. Eur J Neurosci 21:1327–1337.CrossRefPubMedGoogle Scholar
  46. Toyoda H, Ohno K, Yamada J, Ikeda M, Okabe A, Sato K, Hashimoto K, Fukuda A (2003) Induction of NMDA and GABAA receptor-mediated Ca2+ oscillations with KCC2 mRNA downregulation in injured facial motoneurons. J Neurophysiol 89:1353–1362.CrossRefPubMedGoogle Scholar
  47. Ueno T, Okabe A, Akaike N, Fukuda A, Nabekura J (2002) Diversity of neuron-specific K+-Cl cotransporter expression and inhibitory postsynaptic potential depression in rat motoneurons. J Biol Chem 277:4945–4950.CrossRefPubMedGoogle Scholar
  48. Uvarov P, Ludwig A, Markkanen M, Pruunsild P, Kaila K, Delpire E, Timmusk T, Rivera C, Airaksinen MS (2007) A novel N-terminal isoform of the neuron-specific K-Cl cotransporter KCC2. J Biol Chem 282:30570–30576.CrossRefPubMedGoogle Scholar
  49. Uvarov P, Ludwig A, Markkanen M, Soni S, Hübner CA, Rivera C, Airaksinen MS (2009) Coexpression and heteromerization of two neuronal K-Cl cotransporter isoforms in neonatal brain. J Biol Chem 284:13696–13704.CrossRefPubMedGoogle Scholar
  50. Wake H, Watanabe M, Moorhouse AJ, Kanematsu K, Horibe S, Matsukawa N, Asai K, Ojika K, Hirata M, Nabekura J (2007) Early changes in KCC2 phosphorylation in response to neuronal stress results in functional downregulation. J Neurosci 27:1642–1650.CrossRefPubMedGoogle Scholar
  51. Watanabe M, Sakuma Y, Kato M (2009a) GABAA receptors mediate excitation in adult Rat GnRH neurons. Biol Reprod 81:327–332.CrossRefPubMedGoogle Scholar
  52. Watanabe M, Wake H, Moorhouse AJ, Nabekura J (2009b) Clustering of neuronal K+-Clcotransporters in lipid rafts by tyrosine phosphorylation. J Biol Chem 284:27980–27988.CrossRefPubMedGoogle Scholar
  53. Wenz M, Hartmann AM, Friauf E, Nothwang HG (2009) CIP1 is an activator of the K+-Cl cotransporter KCC2. Biochem Biophys Res Commun 381:388–392.CrossRefPubMedGoogle Scholar
  54. Yamada J, Okabe A, Toyoda H, Kilb W, Luhmann HJ, Fukuda A (2004) Cl- uptake promoting depolarizing GABA actions in immature rat neocortical neurones is mediated by NKCC1. J Physiol 557:829–841.CrossRefPubMedGoogle Scholar
  55. Zhao B, Wong AY, Murshid A, Bowie D, Presley JF, Bedford FK (2008) Identification of a novel di-leucine motif mediating K(+)/Cl(−) cotransporter KCC2 constitutive endocytosis. Cell Signal 20:1769–1779.CrossRefPubMedGoogle Scholar
  56. Zhu L, Lovinger D, Delpire E (2005) Cortical neurons lacking KCC2 expression show impaired regulation of intracellular chloride. J Neurophysiol 93:1557–1568.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Membrane Biophysics Laboratory, Department of Physiology, School of Medical SciencesUniversity of New South WalesSydneyAustralia
  2. 2.Division of Homeostatic Development, Department of Developmental PhysiologyNational Institute for Physiological SciencesOkazakiJapan

Personalised recommendations