Skip to main content

Advertisement

SpringerLink
Log in

K-Cl cotransporter KCC2—a moonlighting protein in excitatory and inhibitory synapse development and function

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The K-Cl cotransporter KCC2 has two entirely independent biological actions as either an ion transporter or a structural protein orchestrating the organization of the cytoskeleton in neuronal structures. The K-Cl cotransport by KCC2 is central for hyperpolarizing inhibitory signaling, which is based on chloride currents mediated by γ-aminobutyric acid (GABA)- or glycine-gated receptor channels. In contrast, the structural role of KCC2 seems to be crucially involved in the maturation and regulation of excitatory glutamatergic synapses. This dual role at GABAergic/glycinergic and glutamatergic synapses makes KCC2 a key molecule in the regulation of inhibitory and excitatory signaling. Therefore, KCC2 is most likely involved in the synchronization of the two types of activity during network formation in the immature system and a similar synchronizing role might also be important under physiological and pathological conditions in mature neuronal networks. In this review, we explore new findings on the regulation of KCC2 by protease-mediated cleavage and on the structural role of KCC2 in spine morphogenesis and glutamate receptor clustering. We then discuss the implications of the putative interaction between the independent functions of the transporter and overlapping regulatory mechanisms in a neurophysiological context. In addition, we look at the multifunctional properties of KCC2 in the light of evolution and propose that KCC2 belongs to the group of moonlighting (multifunctional) proteins.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Aickin CC, Deisz RA, Lux HD (1982) Ammonium action on post-synaptic inhibition in crayfish neurones: implications for the mechanism of chloride extrusion. J Physiol 329:319–339

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Balakrishnan V, Becker M, Löhrke S, Nothwang HG, Güresir E, Friauf E (2003) Expression and function of chloride transporters during development of inhibitory neurotransmission in the auditory brainstem. J Neurosci 23:4134–4145

    CAS  PubMed  Google Scholar 

  3. Banke TG, Gegelashvili G (2008) Tonic activation of group I mGluRs modulates inhibitory synaptic strength by regulating KCC2 activity. J Physiol 586:4925–4934

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Baudry M, Chou MM, Bi X (2013) Targeting calpain in synaptic plasticity. Expert Opin Ther Targets 17:579–592

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Beadle GW, Tatum EL (1941) Genetic control of biochemical reactions in neurospora. Proc Natl Acad Sci U S A 27:499–506

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Bellemer A, Hirata T, Romero MF, Koelle MR (2011) Two types of chloride transporters are required for GABA(A) receptor-mediated inhibition in C. elegans. EMBO J 30:1852–1863

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Ben-Ari Y (2002) Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci 3:728–739

    Article  CAS  PubMed  Google Scholar 

  8. Ben-Ari Y, Khalilov I, Kahle KT, Cherubini E (2012) The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist 18:467–486

    Article  PubMed  Google Scholar 

  9. Ben-Ari Y, Woodin MA, Sernagor E, Cancedda L, Vinay L, Rivera C, Legendre P, Luhmann HJ, Bordey A, Wenner P, Fukuda A et al (2012) Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever! Front Cell Neurosci 6:35

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Blaesse P, Airaksinen MS, Rivera C, Kaila K (2009) Cation-chloride cotransporters and neuronal function. Neuron 61:820–838

    Article  CAS  PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. Bos R, Sadlaoud K, Boulenguez P, Buttigieg D, Liabeuf S, Brocard C, Haase G, Bras H, Vinay L (2013) Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2. Proc Natl Acad Sci U S A 110:348–353

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Boulenguez P, Liabeuf S, Bos R, Bras H, Jean-Xavier C, Brocard C, Stil A, Darbon P, Cattaert D, Delpire E, Marsala M et al (2010) Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury. Nat Med 16:302–307

    Article  CAS  PubMed  Google Scholar 

  14. Casula S, Shmukler BE, Wilhelm S, Stuart-Tilley AK, Su W, Chernova MN, Brugnara C, Alper SL (2001) A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-terminal cytoplasmic domains are required for K-Cl cotransport activity. J Biol Chem 276:41870–41878

    Article  CAS  PubMed  Google Scholar 

  15. Chamma I, Chevy Q, Poncer JC, Levi S (2012) Role of the neuronal K-Cl co-transporter KCC2 in inhibitory and excitatory neurotransmission. Front Cell Neurosci 6:5

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Chamma I, Heubl M, Chevy Q, Renner M, Moutkine I, Eugene E, Poncer JC, Levi S (2013) Activity-dependent regulation of the K/Cl transporter KCC2 membrane diffusion, clustering, and function in hippocampal neurons. J Neurosci 33:15488–15503

    Article  CAS  PubMed  Google Scholar 

  17. Chorin E, Vinograd O, Fleidervish I, Gilad D, Herrmann S, Sekler I, Aizenman E, Hershfinkel M (2011) Upregulation of KCC2 activity by zinc-mediated neurotransmission via the mZnR/GPR39 receptor. J Neurosci 31:12916–12926

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Chudotvorova I, Ivanov A, Rama S, Hübner CA, Pellegrino C, Ben Ari Y, Medina I (2005) Early expression of KCC2 in rat hippocampal cultures augments expression of functional GABA synapses. J Physiol 566:671–679

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Copley SD (2012) Moonlighting is mainstream: paradigm adjustment required. Bioessays 34:578–588

    Article  CAS  PubMed  Google Scholar 

  20. De Koninck Y (2007) Altered chloride homeostasis in neurological disorders: a new target. Curr Opin Pharmacol 7:93–99

    Article  PubMed  Google Scholar 

  21. Deeb TZ, Nakamura Y, Frost GD, Davies PA, Moss SJ (2013) Disrupted Cl(-) homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states. Eur J Neurosci 38:2453–2467

    Article  PubMed Central  PubMed  Google Scholar 

  22. Delpire E, Days E, Lewis LM, Mi D, Kim K, Lindsley CW, Weaver CD (2009) Small-molecule screen identifies inhibitors of the neuronal K-Cl cotransporter KCC2. Proc Natl Acad Sci U S A 106:5383–5388

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Delpire E, Mount DB (2002) Human and murine phenotypes associated with defects in cation-chloride cotransport. Annu Rev Physiol 64:803–843

    Article  CAS  PubMed  Google Scholar 

  24. Doshi S, Lynch DR (2009) Calpain and the glutamatergic synapse. Front Biosci (Sch Ed) 1:466–476

    Article  Google Scholar 

  25. Eichler SA, Kirischuk S, Juttner R, Schaefermeier PK, Legendre P, Lehmann TN, Gloveli T, Grantyn R, Meier JC (2008) Glycinergic tonic inhibition of hippocampal neurons with depolarizing GABAergic transmission elicits histopathological signs of temporal lobe epilepsy. J Cell Mol Med 12:2848–2866

    Article  CAS  PubMed  Google Scholar 

  26. Fiumelli H, Briner A, Puskarjov M, Blaesse P, Belem BJ, Dayer AG, Kaila K, Martin JL, Vutskits L (2013) An ion transport-independent role for the cation-chloride cotransporter KCC2 in dendritic spinogenesis in vivo. Cereb Cortex 23:378–388

    Article  PubMed  Google Scholar 

  27. Fiumelli H, Woodin MA (2007) Role of activity-dependent regulation of neuronal chloride homeostasis in development. Curr Opin Neurol 17:81–86

    Article  CAS  Google Scholar 

  28. Gagnon KB, Delpire E (2013) Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically engineered mouse knockouts. Am J Physiol Cell Physiol 304:C693–C714

    Article  PubMed Central  PubMed  Google Scholar 

  29. Gagnon M, Bergeron MJ, Lavertu G, Castonguay A, Tripathy S, Bonin RP, Perez-Sanchez J, Boudreau D, Wang B, Dumas L, Valade I et al (2013) Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat Med 19:1524–1528

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Gamazon ER, Stranger BE (2014) Genomics of alternative splicing: evolution, development and pathophysiology. Hum Genet 133(6):679–687

    Article  CAS  PubMed  Google Scholar 

  31. Gamba G (2005) Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev 85:423–493

    Article  CAS  PubMed  Google Scholar 

  32. Gauvain G, Chamma I, Chevy Q, Cabezas C, Irinopoulou T, Bodrug N, Carnaud M, Levi S, Poncer JC (2011) The neuronal K-Cl cotransporter KCC2 influences postsynaptic AMPA receptor content and lateral diffusion in dendritic spines. Proc Natl Acad Sci U S A 108:15474–15479

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Gulyas AI, Sik A, Payne JA, Kaila K, Freund TF (2001) The KCI cotransporter, KCC2, is highly expressed in the vicinity of excitatory synapses in the rat hippocampus. Eur J Neurosci 13:2205–2217

    Article  CAS  PubMed  Google Scholar 

  34. Hartmann AM, Tesch D, Nothwang HG, Bininda-Emonds OR (2014) Evolution of the cation chloride cotransporter family: ancient origins, gene losses, and subfunctionalization through duplication. Mol Biol Evol 31:434–447

    Article  CAS  PubMed  Google Scholar 

  35. Hekmat-Scafe DS, Lundy MY, Ranga R, Tanouye MA (2006) Mutations in the K+/Cl- cotransporter gene kazachoc (kcc) increase seizure susceptibility in Drosophila. J Neurosci 26:8943–8954

    Article  CAS  PubMed  Google Scholar 

  36. 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Horn Z, Ringstedt T, Blaesse P, Kaila K, Herlenius E (2010) Premature expression of KCC2 in embryonic mice perturbs neural development by an ion transport-independent mechanism. Eur J Neurosci 31:2142–2155

    Article  PubMed  Google Scholar 

  38. Horowitz NH (1948) The one gene-one enzyme hypothesis. Genetics 33:612

    CAS  PubMed  Google Scholar 

  39. 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

    Article  CAS  PubMed  Google Scholar 

  40. Hübner CA, Stein V, Hermans-Borgmeyer I, Meyer T, Ballanyi K, Jentsch TJ (2001) Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron 30:515–524

    Article  PubMed  Google Scholar 

  41. Jeffery CJ (1999) Moonlighting proteins. Trends Biochem Sci 24:8–11

    Article  CAS  PubMed  Google Scholar 

  42. Jeffery CJ (2003) Moonlighting proteins: old proteins learning new tricks. Trends Genet 19:415–417

    Article  CAS  PubMed  Google Scholar 

  43. Jeffery CJ (2009) Moonlighting proteins—an update. Mol BioSyst 5:345–350

    Article  CAS  PubMed  Google Scholar 

  44. Kaczmarek LK (2006) Non-conducting functions of voltage-gated ion channels. Nat Rev Neurosci 7:761–771

    Article  CAS  PubMed  Google Scholar 

  45. Kahle KT, Deeb TZ, Puskarjov M, Silayeva L, Liang B, Kaila K, Moss SJ (2013) Modulation of neuronal activity by phosphorylation of the K-Cl cotransporter KCC2. Trends Neurosci 36:726–737

    Article  CAS  PubMed  Google Scholar 

  46. 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

    Article  CAS  PubMed  Google Scholar 

  47. Kaila K, Ruusuvuori E, Seja P, Voipio J, Puskarjov M (2014) GABA actions and ionic plasticity in epilepsy. Curr Opin Neurobiol 26:34–41

    Article  CAS  PubMed  Google Scholar 

  48. Khirug S, Ahmad F, Puskarjov M, Afzalov R, Kaila K, Blaesse P (2010) A single seizure episode leads to rapid functional activation of KCC2 in the neonatal rat hippocampus. J Neurosci 30:12028–12035

    Article  CAS  PubMed  Google Scholar 

  49. Lamsa KP, Kullmann DM, Woodin MA (2010) Spike-timing dependent plasticity in inhibitory circuits. Front Synaptic Neurosci 2:8

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Lee HH, Deeb TZ, Walker JA, Davies PA, Moss SJ (2011) NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents. Nat Neurosci 14:736–743

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. 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

    Article  CAS  PubMed  Google Scholar 

  52. Li H, Khirug S, Cai C, Ludwig A, Blaesse P, Kolikova J, Afzalov R, Coleman SK, Lauri S, Airaksinen MS, Keinanen K et al (2007) KCC2 interacts with the dendritic cytoskeleton to promote spine development. Neuron 56:1019–1033

    Article  CAS  PubMed  Google Scholar 

  53. Löscher W, Puskarjov M, Kaila K (2013) Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology 69:62–74

    Article  PubMed  Google Scholar 

  54. Markkanen M, Karhunen T, Llano O, Ludwig A, Rivera C, Uvarov P, Airaksinen MS (2013) Distribution of neuronal KCC2a and KCC2b isoforms in mouse CNS. J Comp Neurol 522:1897–1914

    Article  Google Scholar 

  55. Medina I, Friedel P, Rivera C, Kahle KT, Kourdougli N, Uvarov P, Pellegrino C (2014) Current view on the functional regulation of the neuronal K-Cl cotransporter KCC2. Front Cell Neurosci 8:27

    PubMed Central  PubMed  Google Scholar 

  56. Misgeld U, Deisz RA, Dodt HU, Lux HD (1986) The role of chloride transport in postsynaptic inhibition of hippocampal neurons. Science 232:1413–1415

    Article  CAS  PubMed  Google Scholar 

  57. Pathak HR, Weissinger F, Terunuma M, Carlson GC, Hsu FC, Moss SJ, Coulter DA (2007) Disrupted dentate granule cell chloride regulation enhances synaptic excitability during development of temporal lobe epilepsy. J Neurosci 27:14012–14022

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Payne JA, Stevenson TJ, Donaldson LF (1996) Molecular characterization of a putative K-Cl cotransporter in rat brain. A neuronal-specific isoform. J Biol Chem 271:16245–16252

    Article  CAS  PubMed  Google Scholar 

  59. Pellegrino C, Gubkina O, Schaefer M, Becq H, Ludwig A, Mukhtarov M, Chudotvorova I, Corby S, Salyha Y, Salozhin S, Bregestovski P et al (2011) Knocking down of the KCC2 in rat hippocampal neurons increases intracellular chloride concentration and compromises neuronal survival. J Physiol 589:2475–2496

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Price TJ, Cervero F, Gold MS, Hammond DL, Prescott SA (2009) Chloride regulation in the pain pathway. Brain Res Rev 60:149–170

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Puskarjov M, Ahmad F, Kaila K, Blaesse P (2012) Activity-dependent cleavage of the K-Cl cotransporter KCC2 mediated by calcium-activated protease calpain. J Neurosci 32:11356–11364

    Article  CAS  PubMed  Google Scholar 

  62. Puskarjov M, Seja P, Heron SE, Williams TC, Ahmad F, Iona X, Oliver KL, Grinton BE, Vutskits L, Scheffer IE, Petrou S et al (2014) A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. EMBO Rep. doi:10.1002/embr.201438749

    PubMed  Google Scholar 

  63. Raimondo JV, Markram H, Akerman CJ (2012) Short-term ionic plasticity at GABAergic synapses. Front Synaptic Neurosci 4:5

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. 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

    Article  CAS  PubMed  Google Scholar 

  66. Rivera C, Voipio J, Thomas-Crusells J, Li H, Emri Z, Sipilä 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

    Article  CAS  PubMed  Google Scholar 

  67. Royle SJ (2013) Protein adaptation: mitotic functions for membrane trafficking proteins. Nat Rev Mol Cell Biol 14:592–599

    Article  CAS  PubMed  Google Scholar 

  68. Saadi RA, He K, Hartnett KA, Kandler K, Hershfinkel M, Aizenman E (2012) SNARE-dependent upregulation of potassium chloride co-transporter 2 activity after metabotropic zinc receptor activation in rat cortical neurons in vitro. Neuroscience 210:38–46

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Seja P, Schonewille M, Spitzmaul G, Badura A, Klein I, Rudhard Y, Wisden W, Hübner CA, De Zeeuw CI, Jentsch TJ (2012) Raising cytosolic Cl(-) in cerebellar granule cells affects their excitability and vestibulo-ocular learning. EMBO J 31:1217–1230

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Sriram G, Martinez JA, McCabe ERB, Liao JC, Dipple KM (2005) Single-gene disorders: What role could moonlighting enzymes play? Am J Hum Genet 76:911–924

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Tanis JE, Bellemer A, Moresco JJ, Forbush B, Koelle MR (2009) The potassium chloride cotransporter KCC-2 coordinates development of inhibitory neurotransmission and synapse structure in Caenorhabditis elegans. J Neurosci 29:9943–9954

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Thompson SM, Deisz RA, Prince DA (1988) Outward chloride/cation co-transport in mammalian cortical neurons. Neurosci Lett 89:49–54

    Article  CAS  PubMed  Google Scholar 

  73. Tyagarajan SK, Ghosh H, Yevenes GE, Nikonenko I, Ebeling C, Schwerdel C, Sidler C, Zeilhofer HU, Gerrits B, Muller D, Fritschy JM (2011) Regulation of GABAergic synapse formation and plasticity by GSK3beta-dependent phosphorylation of gephyrin. Proc Natl Acad Sci U S A 108:379–384

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. 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

    Article  CAS  PubMed  Google Scholar 

  75. 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Wake H, Watanabe M, Moorhouse AJ, Kanematsu T, Horibe S, Matsukawa N, Asai K, Ojika K, Hirata M, Nabekura J (2007) Early changes in KCC2 phosphorylation in response to neuronal stress result in functional downregulation. J Neurosci 27:1642–1650

    Article  CAS  PubMed  Google Scholar 

  77. Watanabe M, Wake H, Moorhouse AJ, Nabekura J (2009) Clustering of neuronal K+-Cl- cotransporters in lipid rafts by tyrosine phosphorylation. J Biol Chem 284:27980–27988

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Wei WC, Akerman CJ, Newey SE, Pan J, Clinch NW, Jacob Y, Shen MR, Wilkins RJ, Ellory JC (2011) The potassium-chloride cotransporter 2 promotes cervical cancer cell migration and invasion by an ion transport-independent mechanism. J Physiol 589:5349–5359

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Woo NS, Lu JM, England R, McClellan R, Dufour S, Mount DB, Deutch AY, Lovinger DM, Delpire E (2002) Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K-Cl cotransporter gene. Hippocampus 12:258–268

    Article  CAS  PubMed  Google Scholar 

  80. Woodin MA, Ganguly K, Poo MM (2003) Coincident pre- and postsynaptic activity modifies GABAergic synapses by postsynaptic changes in Cl- transporter activity. Neuron 39:807–820

    Article  CAS  PubMed  Google Scholar 

  81. Yuste R (2013) Electrical compartmentalization in dendritic spines. Annu Rev Neurosci 36:429–449

    Article  CAS  PubMed  Google Scholar 

  82. Zadran S, Akopian G, Zadran H, Walsh J, Baudry M (2013) RVG-mediated calpain2 gene silencing in the brain impairs learning and memory. Neuromol Med 15:74–81

    Article  CAS  Google Scholar 

  83. Zadran S, Jourdi H, Rostamiani K, Qin Q, Bi X, Baudry M (2010) Brain-derived neurotrophic factor and epidermal growth factor activate neuronal m-calpain via mitogen-activated protein kinase-dependent phosphorylation. J Neurosci 30:1086–1095

    Article  CAS  PubMed  Google Scholar 

  84. Zadran S, Qin Q, Bi X, Zadran H, Kim Y, Foy MR, Thompson R, Baudry M (2009) 17-Beta-estradiol increases neuronal excitability through MAP kinase-induced calpain activation. Proc Natl Acad Sci U S A 106:21936–21941

    Article  PubMed Central  PubMed  Google Scholar 

  85. Zhou HY, Chen SR, Byun HS, Chen H, Li L, Han HD, Lopez-Berestein G, Sood AK, Pan HL (2012) N-methyl-D-aspartate receptor- and calpain-mediated proteolytic cleavage of K+-Cl- cotransporter-2 impairs spinal chloride homeostasis in neuropathic pain. J Biol Chem 287:33853–33864

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Zhu L, Lovinger D, Delpire E (2005) Cortical neurons lacking KCC2 expression show impaired regulation of intracellular chloride. J Neurophysiol 93:1557–1568

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

We thank Drs. K. Jüngling, K. Kaila, H. G. Nothwang, H.-C. Pape, and S. Sivakumaran for their constructive comments on an earlier version of the manuscript.

Author information

Authors and Affiliations

  1. Institute of Physiology I (Neurophysiology), Westfälische Wilhelms-University Münster, Robert-Koch-Strasse 27a, 48149, Münster, Germany

    Peter Blaesse

  2. Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany

    Tobias Schmidt

Authors
  1. Peter Blaesse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tobias Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Blaesse.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blaesse, P., Schmidt, T. K-Cl cotransporter KCC2—a moonlighting protein in excitatory and inhibitory synapse development and function. Pflugers Arch - Eur J Physiol 467, 615–624 (2015). https://doi.org/10.1007/s00424-014-1547-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-014-1547-6

Keywords

Search

Navigation