Abstract
Astrocytes utilize two major pathways to achieve long distance intercellular communication. One pathway involves direct gap junction mediated signal transmission and the other consists of release of ATP through pannexin channels and excitation of purinergic receptors on nearby cells. Elevated extracellular potassium to levels occurring around hyperactive neurons affects both gap junction and pannexin1 channels. The action on Cx43 gap junctions is to increase intercellular coupling for a period that long outlasts the stimulus. This long term increase in coupling, termed “LINC”, is mediated through calcium and calmodulin dependent activation of calmodulin dependent kinase (CaMK). Pannexin1 can be activated by elevations in extracellular potassium through a mechanism that is quite different. In this case, potassium shifts activation potentials to more physiological range, thereby allowing channel opening at resting or slightly depolarized potentials. Enhanced activity of both these channel types by elevations in extracellular potassium of the magnitude occurring during periods of high neuronal activity likely has profound effects on intercellular signaling among astrocytes in the nervous system.
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References
Singer W, Lux HD (1975) Extracellular potassium gradients and visual receptive fields in the cat striate cortex. Brain Res 96(2):378–383
Katzman R (1976) Maintenance of a constant brain extracellular potassium. Fed Proc 35(6):1244–1247
Connors B et al (1979) LSD’s effect on neuron populations in visual cortex gauged by transient responses of extracellular potassium evoked by optical stimuli. Neurosci Lett 13(2):147–150
Somjen GG (1979) Extracellular potassium in the mammalian central nervous system. Annu Rev Physiol 41:159–177
Heinemann U, Lux HD (1977) Ceiling of stimulus induced rises in extracellular potassium concentration in the cerebral cortex of cat. Brain Res 120(2):231–249
Gutnick MJ, Heinemann U, Lux HD (1979) Stimulus induced and seizure related changes in extracellular potassium concentration in cat thalamus (VPL). Electroencephalogr Clin Neurophysiol 47(3):329–344
Karwoski CJ et al (1985) Light-evoked increases in extracellular K+ in the plexiform layers of amphibian retinas. J Gen Physiol 86(2):189–213
Ransom BR, Carlini WG, Connors BW (1986) Brain extracellular space: developmental studies in rat optic nerve. Ann N Y Acad Sci 481:87–105
Frishman LJ et al (1992) Light-evoked changes in [K+]o in proximal portion of light-adapted cat retina. J Neurophysiol 67(5):1201–1212
Heinemann U, Schaible HG, Schmidt RF (1990) Changes in extracellular potassium concentration in cat spinal cord in response to innocuous and noxious stimulation of legs with healthy and inflamed knee joints. Exp Brain Res 79(2):283–292
Vyskocil F, Kritz N, Bures J (1972) Potassium-selective microelectrodes used for measuring the extracellular brain potassium during spreading depression and anoxic depolarization in rats. Brain Res 39(1):255–259
Somjen GG (2002) Ion regulation in the brain: implications for pathophysiology. Neuroscientist 8(3):254–267
Astrup J, Norberg K (1976) Potassium activity in cerebral cortex in rats during progressive severe hypoglycemia. Brain Res 103(2):418–423
Blank WF Jr, Kirshner HS (1977) The kinetics of extracellular potassium changes during hypoxia and anoxia in the cat cerebral cortex. Brain Res 123(1):113–124
Kofuji P, Newman EA (2004) Potassium buffering in the central nervous system. Neuroscience 129(4):1045–1056
Orkand RK, Nicholls JG, Kuffler SW (1966) Effect of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia. J Neurophysiol 29(4):788–806
Somjen GG (2001) Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 81(3):1065–1096
Pasantes-Morales H, Schousboe A (1989) Release of taurine from astrocytes during potassium-evoked swelling. Glia 2(1):45–50
Walz W (1997) Role of astrocytes in the spreading depression signal between ischemic core and penumbra. Neurosci Biobehav Rev 21(2):135–142
Huang R et al (1994) Signalling effect of elevated potassium concentrations and monoamines on brain energy metabolism at the cellular level. Dev Neurosci 16(5–6):337–351
Chesler M, Kraig RP (1987) Intracellular pH of astrocytes increases rapidly with cortical stimulation. Am J Physiol 253(4 Pt 2):R666–R670
Chesler M, Kraig RP (1989) Intracellular pH transients of mammalian astrocytes. J Neurosci 9(6):2011–2019
Deitmer JW, Szatkowski M (1990) Membrane potential dependence of intracellular pH regulation by identified glial cells in the leech central nervous system. J Physiol 421:617–631
Pappas CA, Ransom BR (1994) Depolarization-induced alkalinization (DIA) in rat hippocampal astrocytes. J Neurophysiol 72(6):2816–2826
Ruminot I et al (2011) NBCe1 mediates the acute stimulation of astrocytic glycolysis by extracellular K+. J Neurosci 31(40):14264–14271
Kaufman EE, Driscoll BF (1992) Carbon dioxide fixation in neuronal and astroglial cells in culture. J Neurochem 58(1):258–262
Subbarao KV, Stolzenburg JU, Hertz L (1995) Pharmacological characteristics of potassium-induced, glycogenolysis in astrocytes. Neurosci Lett 196(1–2):45–48
De Pina-Benabou MH et al (2001) Calmodulin kinase pathway mediates the K+-induced increase in Gap junctional communication between mouse spinal cord astrocytes. J Neurosci 21(17):6635–6643
Baranova A et al (2004) The mammalian pannexin family is homologous to the invertebrate innexin gap junction proteins. Genomics 83(4):706–716
Panchin Y et al (2000) A ubiquitous family of putative gap junction molecules. Curr Biol 10(13):R473–R474
Sosinsky GE et al (2011) Pannexin channels are not gap junction hemichannels. Channels (Austin) 5(3):193–197
Rochefort N et al (2005) Postnatal development of GFAP, connexin43 and connexin30 in cat visual cortex. Brain Res Dev Brain Res 160(2):252–264
Koulakoff A, Ezan P, Giaume C (2008) Neurons control the expression of connexin 30 and connexin 43 in mouse cortical astrocytes. Glia 56(12):1299–1311
Cotrina ML et al (2001) Expression and function of astrocytic gap junctions in aging. Brain Res 901(1–2):55–61
Rash JE et al (2001) Identification of cells expressing Cx43, Cx30, Cx26, Cx32 and Cx36 in gap junctions of rat brain and spinal cord. Cell Commun Adhes 8(4–6):315–320
Wang J et al (2007) Modulation of membrane channel currents by gap junction protein mimetic peptides: size matters. Am J Physiol Cell Physiol 293(3):C1112–C1119
Simpson I, Rose B, Loewenstein WR (1977) Size limit of molecules permeating the junctional membrane channels. Science 195(4275):294–296
Walz W, Hertz L (1982) Ouabain-sensitive and ouabain-resistant net uptake of potassium into astrocytes and neurons in primary cultures. J Neurochem 39(1):70–77
Walz W, Hertz L (1984) Intense furosemide-sensitive potassium accumulation in astrocytes in the presence of pathologically high extracellular potassium levels. J Cereb Blood Flow Metab 4(2):301–304
Kempski O et al (1991) Glial ion transport and volume control. Ann N Y Acad Sci 633:306–317
Higashi K et al (2001) An inwardly rectifying K+ channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain. Am J Physiol Cell Physiol 281(3):C922–C931
Hibino H et al (2004) Differential assembly of inwardly rectifying K+ channel subunits, Kir4.1 and Kir5.1, in brain astrocytes. J Biol Chem 279(42):44065–44073
Kofuji P et al (2000) Genetic inactivation of an inwardly rectifying potassium channel (Kir4.1 subunit) in mice: phenotypic impact in retina. J Neurosci 20(15):5733–5740
Xiong ZQ, Stringer JL (1999) Cesium induces spontaneous epileptiform activity without changing extracellular potassium regulation in rat hippocampus. J Neurophysiol 82(6):3339–3346
D’Ambrosio R, Gordon DS, Winn HR (2002) Differential role of KIR channel and Na(+)/K(+)-pump in the regulation of extracellular K+ in rat hippocampus. J Neurophysiol 87(1):87–102
Chever O et al (2010) Implication of Kir4.1 channel in excess potassium clearance: an in vivo study on anesthetized glial-conditional Kir4.1 knock-out mice. J Neurosci 30(47):15769–15777
Kuffler SW, Nicholls JG, Orkand RK (1966) Physiological properties of glial cells in the central nervous system of amphibia. J Neurophysiol 29(4):768–787
Somjen GG (1975) Electrophysiol Neuroglia. Annu Rev Physiol 37:163–190
Amzica F, Steriade M (2000) Neuronal and glial membrane potentials during sleep and paroxysmal oscillations in the neocortex. J Neurosci 20(17):6648–6665
Amzica F, Massimini M, Manfridi A (2002) Spatial buffering during slow and paroxysmal sleep oscillations in cortical networks of glial cells in vivo. J Neurosci 22(3):1042–1053
Gardner-Medwin AR (1983) Analysis of potassium dynamics in mammalian brain tissue. J Physiol 335:393–426
Gardner-Medwin AR (1983) A study of the mechanisms by which potassium moves through brain tissue in the rat. J Physiol 335:353–374
Dermietzel R et al (1991) Gap junctions between cultured astrocytes: immunocytochemical, molecular, and electrophysiological analysis. J Neurosci 11(5):1421–1432
Dermietzel R et al (2000) Connexin43 null mice reveal that astrocytes express multiple connexins. Brain Res Brain Res Rev 32(1):45–56
Nagy JI, Rash JE (2000) Connexins and gap junctions of astrocytes and oligodendrocytes in the CNS. Brain Res Brain Res Rev 32(1):29–44
Scemes E, Suadicani SO, Spray DC (2000) Intercellular communication in spinal cord astrocytes: fine tuning between gap junctions and P2 nucleotide receptors in calcium wave propagation. J Neurosci 20(4):1435–1445
Xu G et al (2010) Electrical coupling of astrocytes in rat hippocampal slices under physiological and simulated ischemic conditions. Glia 58(4):481–493
Newman EA (1984) Regional specialization of retinal glial cell membrane. Nature 309(5964):155–157
Newman EA (1993) Inward-rectifying potassium channels in retinal glial (Muller) cells. J Neurosci 13(8):3333–3345
Wallraff A et al (2006) The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J Neurosci 26(20):5438–5447
Enkvist MO, McCarthy KD (1994) Astroglial gap junction communication is increased by treatment with either glutamate or high K+ concentration. J Neurochem 62(2):489–495
Roux L et al (2011) Plasticity of astroglial networks in olfactory glomeruli. Proc Natl Acad Sci USA 108(45):18442–18446
Nagy JI, Li WE (2000) A brain slice model for in vitro analyses of astrocytic gap junction and connexin43 regulation: actions of ischemia, glutamate and elevated potassium. Eur J Neurosci 12(12):4567–4572
Li WE, Nagy JI (2000) Activation of fibres in rat sciatic nerve alters phosphorylation state of connexin-43 at astrocytic gap junctions in spinal cord: evidence for junction regulation by neuronal-glial interactions. Neuroscience 97(1):113–123
Revilla A, Bennett MV, Barrio LC (2000) Molecular determinants of membrane potential dependence in vertebrate gap junction channels. Proc Natl Acad Sci USA 97(26):14760–14765
Spray DC, Harris AL, Bennett MV (1981) Equilibrium properties of a voltage-dependent junctional conductance. J Gen Physiol 77(1):77–93
Francis D et al (1999) Connexin diversity and gap junction regulation by pHi. Dev Genet 24(1–2):123–136
MacVicar BA (1984) Voltage-dependent calcium channels in glial cells. Science 226(4680):1345–1347
MacVicar BA et al (1991) Modulation of intracellular Ca++ in cultured astrocytes by influx through voltage-activated Ca++ channels. Glia 4(5):448–455
Duffy S, MacVicar BA (1994) Potassium-dependent calcium influx in acutely isolated hippocampal astrocytes. Neuroscience 61(1):51–61
Westenbroek RE et al (1998) Upregulation of L-type Ca2+ channels in reactive astrocytes after brain injury, hypomyelination, and ischemia. J Neurosci 18(7):2321–2334
Scemes E et al (2007) Connexin and pannexin mediated cell–cell communication. Neuron Glia Biol 3(3):199–208
Scemes E, Spray DC, Meda P (2009) Connexins, pannexins, innexins: novel roles of “hemi-channels”. Pflugers Arch 457(6):1207–1226
Silverman WR et al (2009) The pannexin 1 channel activates the inflammasome in neurons and astrocytes. J Biol Chem 284(27):18143–18151
Santiago MF et al (2011) Targeting pannexin1 improves seizure outcome. PLoS ONE 6(9):e25178
Scemes E (2000) Components of astrocytic intercellular calcium signaling. Mol Neurobiol 22(1–3):167–179
Scemes E, Giaume C (2006) Astrocyte calcium waves: what they are and what they do. Glia 54(7):716–725
Suadicani SO, Brosnan CF, Scemes E (2006) P2X7 receptors mediate ATP release and amplification of astrocytic intercellular Ca2+ signaling. J Neurosci 26(5):1378–1385
Suadicani SO et al (2003) Acute downregulation of Cx43 alters P2Y receptor expression levels in mouse spinal cord astrocytes. Glia 42(2):160–171
Pereda AE et al (2004) Dynamics of electrical transmission at club endings on the Mauthner cells. Brain Res Brain Res Rev 47(1–3):227–244
Alev C et al (2008) The neuronal connexin36 interacts with and is phosphorylated by CaMKII in a way similar to CaMKII interaction with glutamate receptors. Proc Natl Acad Sci USA 105(52):20964–20969
Chen KC, Nicholson C (2000) Spatial buffering of potassium ions in brain extracellular space. Biophys J 78(6):2776–2797
Walz W (2000) Role of astrocytes in the clearance of excess extracellular potassium. Neurochem Int 36(4–5):291–300
Scemes E (2008) Modulation of astrocyte P2Y1 receptors by the carboxyl terminal domain of the gap junction protein Cx43. Glia 56(2):145–153
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The work of Drs Scemes and Spray is supported by NIH (RO1-NS052245 (ES) and RO1-NS04128 (DCS).
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Special Issue: In honor of Leif Hertz.
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Scemes, E., Spray, D.C. Extracellular K+ and Astrocyte Signaling via Connexin and Pannexin Channels. Neurochem Res 37, 2310–2316 (2012). https://doi.org/10.1007/s11064-012-0759-4
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DOI: https://doi.org/10.1007/s11064-012-0759-4