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Link to original content: https://doi.org/10.1038/35077553
Neuromodulation of Na+ channels: An unexpected form of cellular platicity | Nature Reviews Neuroscience
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  • Review Article
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Neuromodulation of Na+ channels: An unexpected form of cellular platicity

Nature Reviews Neuroscience volume 2, pages 397–407 (2001)Cite this article

Key Points

  • Voltage-gated Na+ channels consist of an α subunit in association with auxiliary β subunits. The α subunits consist of four homologous domains, each of which contains six transmembrane segments and a membrane re-entrant loop between S5 and S6. The S4 segments serve as the voltage sensors, the S5 and S6 segments and the re-entrant loop form the lining of the pore, and the short intracellular loop between domains III and IV forms the inactivation gate.

  • Voltage-gated Na+ channels are prime candidates for mediating cellular plasticity because they set the threshold for action potential generation. Analyses of Na+ channel regulation have revealed the molecular mechanism of neuromodulation of Na+ channels by protein phosphorylation via the cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) pathways.

  • Modulation of Na+ channels is implicated in the control of input–output relationships in several types of neuron including striatal, hippocampal, and cortical cells. Activation of several G-protein-coupled receptors that stimulate PKA and PKC can affect the functionality of native Na+ currents.

  • Na+-channel modulation is likely to be related to different aspects of nervous system physiology. For example, cocaine treatment and withdrawal can modulate Na+ channel function and hyeralgesia can lead to upregulation of Na+ channel activity. Furthermore, alteration of action potential generation in retinal ganglion neurons during contrast adaptation is likely to involve the modulation of Na+ channels.

Abstract

Voltage-gated Na+ channels set the threshold for action potential generation and are therefore good candidates to mediate forms of plasticity that affect the entire neuronal output. Although early studies led to the idea that Na+ channels were not subject to modulation, we now know that Na+ channel function is affected by phosphorylation. Furthermore, Na+ channel modulation is implicated in the control of input–output relationships in several types of neuron and seems to be involved in phenomena as varied as cocaine withdrawal, hyperalgesia and light adaptation. Here we review the available evidence for the regulation of Na+ channels by phosphorylation, its molecular mechanism, and the possible ways in which it affects neuronal function.

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Figure 1: Neurotransmitter pathways that modulate Na+ channels in hippocampal neurons.
Figure 2: Phosphorylation of Na+ channels and its functional effect in synaptosomes.
Figure 3: Contrasting effects of PKA modulation on Na+ currents in hippocampal and dorsal root ganglion neurons.
Figure 4: Changes in firing properties of neurons accompanying neuromodulation of Na+ channels.

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References

  1. Luscher, C., Nicoll, R. A., Malenka, R. C. & Muller, D. Synaptic plasticity and dynamic modulation of the postsynaptic membrane. Nature Neurosci. 3, 545–550 (2000).

    CAS  PubMed  Google Scholar 

  2. Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    CAS  PubMed  Google Scholar 

  3. Hausser, M., Spruston, N. & Stuart, G. J. Diversity and dynamics of dendritic signaling. Science 290, 739–744 (2000).

    CAS  PubMed  Google Scholar 

  4. Stuart, G. J., Spruston, N., Sakmann, B. & Hausser, M. Action potential initiation and backpropagation in neurons of the mammalian CNS. Trends Neurosci. 20, 125–131 (1997).

    CAS  PubMed  Google Scholar 

  5. Baranauskas, G. & Nistri, A. Sensitization of pain pathways in the spinal cord: cellular mechanisms. Prog. Neurobiol. 54, 349–365 (1998).

    CAS  PubMed  Google Scholar 

  6. Crill, W. E. The effectiveness of distal synaptic inputs on neurons. Ann. NY Acad. Sci. 835, 77–82 (1997).

    CAS  PubMed  Google Scholar 

  7. Hodgkin, A. L., Huxley, A. F. & Katz, B. Measurement of current-voltage relations in the membrane of the giant axon of Loligo. J. Physiol. 116, 424–448 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hille,B. Ionic Channels of Excitable Membranes 70–75 (Sinauer, Sunderland, 1984).

    Google Scholar 

  9. Catterall, W. A. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26, 13–25 (2000).

    CAS  PubMed  Google Scholar 

  10. Catterall, W. A. Cellular and molecular biology of voltage-gated sodium channels. Physiol. Rev. 72, S15–48 (1992).

    CAS  PubMed  Google Scholar 

  11. Catterall, W. A. The molecular basis of neuronal excitability. Science 223, 653–661 (1984).

    CAS  PubMed  Google Scholar 

  12. Goldin, A. L. et al. Nomenclature of voltage-gated sodium channels. Neuron 28, 365–368 (2000) .A brief, but complete review of voltage-gated sodium channel heterogeneity and current nomenclature. | PubMed |

    CAS  PubMed  Google Scholar 

  13. Numa, S. & Noda, M. Molecular structure of sodium channels. Ann. NY Acad. Sci. 479, 338–355 (1986).

    CAS  PubMed  Google Scholar 

  14. Noda, M. et al. Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312, 121–127 (1984).

    CAS  PubMed  Google Scholar 

  15. Noda, M. et al. Expression of functional sodium channels from cloned cDNA. Nature 322, 826–828 (1986).

    CAS  PubMed  Google Scholar 

  16. Goldin, A. L. et al. Messenger RNA coding for only the α subunit of the rat brain sodium channel is sufficient for expression of functional channels in Xenopus oocytes. Proc. Natl Acad. Sci. USA 83, 7503–7507 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Scheuer, T. et al. Functional properties of rat brain sodium channels expressed in a somatic cell line. Science 247, 854–858 (1990).

    CAS  PubMed  Google Scholar 

  18. Isom, L. L. et al. Primary structure and functional expression of the β1 subunit of the rat brain sodium channel. Science 256, 839–842 (1992).

    CAS  PubMed  Google Scholar 

  19. Isom, L. L. et al. Structure and function of the β2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell 83, 433–442 (1995).

    CAS  PubMed  Google Scholar 

  20. Isom, L. L. et al. Functional co-expression of the β1 and type IIA α subunits of sodium channels in a mammalian cell line. J. Biol. Chem. 270, 3306–3312 (1995).

    CAS  PubMed  Google Scholar 

  21. Morgan, K. et al. β3: an additional auxiliary subunit of the voltage-sensitive sodium channels that modulates channel gating with distinct kinetics. Proc. Natl Acad. Sci. USA 97, 2308–2313 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Costa, M. R., Casnellie, J. E. & Catterall, W. A. Selective phosphorylation of the α subunit of the sodium channel in synaptic nerve ending particles. J. Biol. Chem. 257, 7918–7921 (1982).

    CAS  PubMed  Google Scholar 

  23. Costa, M. R. & Catterall, W. A. Cyclic AMP-dependent phosphorylation of the α subunit of the sodium channel in synaptic nerve ending particles. J. Biol. Chem. 259, 8210–8218 (1984).

    CAS  PubMed  Google Scholar 

  24. Costa, M. R. & Catterall, W. A. Phosphorylation of the alpha subunit of the sodium channel by protein kinase C. Cell Mol. Neurobiol. 4, 291–297 (1984).References 23 and 24 present biochemical experiments showing that voltage-gated sodium channels in synaptosomes are excellent substrates for phosphorylation by PKA and PKC and are inhibited by phosphorylation.

    CAS  PubMed  Google Scholar 

  25. Murphy, B. J. & Catterall, W. A. Phosphorylation of purified rat brain Na+ channel reconstituted into phospholipid vesicles by protein kinase C. J. Biol. Chem. 267, 16129–16134 (1992).

    CAS  PubMed  Google Scholar 

  26. Rossie, S. & Catterall, W. A. Cyclic AMP-dependent phosphorylation of voltage-sensitive sodium channels in primary cultures of rat brain neurons. J. Biol. Chem. 262, 12735–12744 (1987).

    CAS  PubMed  Google Scholar 

  27. Rossie, S., Gordon, D. & Catterall, W. A. Identification of an intracellular domain of the sodium channel having multiple cAMP-dependent phosphorylation sites. J. Biol. Chem. 262, 17530–17535 (1987).

    CAS  PubMed  Google Scholar 

  28. Rossie, S. & Catterall, W. A. Phosphorylation of the α subunit of rat brain sodium channels by cAMP-dependent protein kinase at a new site containing ser686 and ser687. J. Biol. Chem. 264, 14220–14224 (1989).

    CAS  PubMed  Google Scholar 

  29. Murphy, B. J., Rossie, S., DeJongh, K. S. & Catterall, W. A. Identification of the sites of selective phosphorylation and dephosphorylation of the rat brain sodium channel α subunit by cAMP-dependent protein kinase and phosphoprotein phosphatases. J. Biol. Chem. 268, 27355–27362 (1993).

    CAS  PubMed  Google Scholar 

  30. Chen, T.-C., Law, B., Kondratyuk, T. & Rossie, S. Identification of soluble protein phosphatases that dephosphorylate voltage-sensitive sodium channels in rat brain. J. Biol. Chem. 270, 7750–7756 (1995).

    CAS  PubMed  Google Scholar 

  31. Numann, R., Catterall, W. A. & Scheuer, T. Functional modulation of brain sodium channels by protein kinase C phosphorylation. Science 254, 115–118 (1991).

    CAS  PubMed  Google Scholar 

  32. Gershon, E., Weigl, L., Lotan, I., Schreibmayer, W. & Dascal, N. Protein kinase A reduces voltage-dependent sodium current in Xenopus oocytes. J. Neurosci. 12, 3743–3752 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Schreibmayer, W., Dascal, N., Lotan, I., Wallner, M. & Weigl, L. Molecular mechanisms of protein kinase C modulation of sodium channel α-subunits expressed in Xenopus oocytes. FEBS Lett. 291, 341–344 (1991).

    CAS  PubMed  Google Scholar 

  34. Li, M., West, J. W., Lai, Y., Scheuer, T. & Catterall, W. A. Functional modulation of brain sodium channels by cAMP-dependent phosphorylation. Neuron 8, 1151–1159 (1992).References 31 and 34 demonstrate the functional modulation of sodium channels in brain neurons by PKA and PKC.

    CAS  PubMed  Google Scholar 

  35. Smith, R. D. & Goldin, A. L. Functional analysis of the Rat I sodium channel in Xenopus oocytes. J. Neurosci. 18, 811–820 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Smith, R. D. & Goldin, A. L. Phosphorylation of brain sodium channels in the I-II linker modulates channel function in Xenopus oocytes. J. Neurosci. 16, 1965–1974 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Smith, R. D. & Goldin, A. L. Phosphorylation at a single site in the brain sodium channel is necessary and sufficient for current reduction by protein kinase A. J. Neurosci. 17, 6086–6093 (1997).References 29, 36 and 37 , and reference 46 below, identified the sites of regulation of sodium channels by PKA phosphorylation.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sigel, E. & Baur, R. Activation of protein kinase C differentially modulates neuronal sodium, calcium and GABA type A channels. Proc. Natl Acad. Sci. USA 85, 6192–6196 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Dascal, N. & Lotan, I. Activation of protein kinase C alters the voltage-dependence of sodium channel. Neuron 6, 165–175 (1991).

    CAS  PubMed  Google Scholar 

  40. Godoy, C. M. & Cukierman, S. Diacylglycerol-induced activation of protein kinase C attenuates Na+ currents by enhancing inactivation from the closed state. Pflugers Arch. 429, 245–252 (1994).

    CAS  PubMed  Google Scholar 

  41. Cantrell, A. R., Smith, R. D., Goldin, A. L., Scheuer, T. & Catterall, W. A. Dopaminergic modulation of sodium current in hippocampal neurons via cAMP-dependent phosphorylation of specific sites in the sodium channel α subunit. J. Neurosci. 17, 7330–7338 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Cantrell, A. R. et al. Molecular mechanisms underlying convergent regulation of brain Na+ channels by Protein Kinase A and Protein Kinase C. Soc. Neurosci. Abstr. 26, 1908 (2000).

  43. West, J. W., Numann, R., Murphy, B. J., Scheuer, T. & Catterall, W. A. A phosphorylation site in the sodium channels required for modulation by protein kinase C. Science 254, 866–868 (1991).

    CAS  PubMed  Google Scholar 

  44. West, J. W., Numann, R., Murphy, B. J., Scheuer, T. & Catterall, W. A. Phosphorylation of a conserved protein kinase C site is required for modulation of Na+ currents in transfected Chinese hamster ovary cells. Biophys. J. 62, 31–33 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Li, M. et al. Convergent regulation of sodium channels by protein kinase C and cAMP-dependent protein kinase. Science 261, 1439–1442 (1993).Demonstration of convergent regulation of brain sodium channels by PKC and PKA.

    CAS  PubMed  Google Scholar 

  46. Cantrell, A. R., Scheuer, T. & Catterall, W. A. Voltage-dependent neuromodulation of Na+ channels by D1-like dopamine receptors in rat hippocampal neurons. J. Neurosci. 19, 5301–5310 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Cantrell, A. R., Ma, J. Y., Scheuer, T. & Catterall, W. A. Muscarinic modulation of sodium current by activation of protein kinase C in rat hippocampal neurons. Neuron 16, 1019–1026 (1996).References 41, 46 and 47 demonstrate neurotransmitter receptor activation resulting in voltage-, PKA- and PKC-dependent modulation of neuronal sodium channels.

    CAS  PubMed  Google Scholar 

  48. Kubo, T. et al. Cloning, sequencing and expression of complementary DNA encoding the muscarinic acetylcholine receptor. Nature 323, 411–416 (1986).

    CAS  PubMed  Google Scholar 

  49. Bonner, T. I., Buckley, N. J., Young, A. C. & Brann, M. Identification of a family of muscarinic acetylcholine receptor genes. Science 237, 527–531 (1987).

    CAS  PubMed  Google Scholar 

  50. Bonner, T. I., Young, A. C., Brann, M. & Buckley, N. J. Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. Neuron 1, 403–410 (1988).

    CAS  PubMed  Google Scholar 

  51. Liao, C. F. et al. Molecular cloning and expression of a fifth muscarinic acetylcholine receptor. J. Biol. Chem. 264, 7328–7337 (1989).

    CAS  PubMed  Google Scholar 

  52. Hulme, E. C., Birdsall, N. M. J. & Buckley, N. J. Muscarinic receptor subtypes. Annu. Rev. Pharmacol. Toxicol. 30, 633–673 (1990).

    CAS  PubMed  Google Scholar 

  53. Nathanson, N. M. Molecular properties of the muscarinic acetylcholine receptor. Annu. Rev. Neurosci. 10, 195–236 (1987).

    CAS  PubMed  Google Scholar 

  54. Meador-Woodruff, J. H. et al. Dopamine receptor gene expression in the human medial temporal lobe. Neuropsychopharmacology 10, 239–248 (1994).

    CAS  PubMed  Google Scholar 

  55. Stoof, J. C. & Kebabian, J. W. Opposing roles for D1 and D2 dopamine receptors in the efflux of cyclic AMP from rat neostriatum. Nature 294, 366–368 (1981).

    CAS  PubMed  Google Scholar 

  56. Stoof, J. C. & Kebabian, J. W. Two dopamine receptors: biochemistry, physiology and pharmacology. Life Sci. 35, 2281–2296 (1984).

    CAS  PubMed  Google Scholar 

  57. Sibley, D. R. & Monsma, F. J. Molecular biology of dopamine receptors. Trends Pharmacol. Sci. 13, 61–75 (1992).

    CAS  PubMed  Google Scholar 

  58. O'Dowd, B. F. Structures of dopamine receptors. J. Neurochem. 60, 804–806 (1993).

    CAS  PubMed  Google Scholar 

  59. Cantrell, A. R., Tibbs, V. C., Westenbroek, R. E., Scheuer, T. & Catterall, W. A. Dopaminergic modulation of voltage-gated Na+ current in rat hippocampal neurons requires anchoring of cAMP-dependent protein kinase. J. Neurosci. 19, RC21 (1999).

  60. Hornykiewcz, O. Dopamine in the basal ganglia. Its role and therapeutic implications (including the clinical use of l-DOPA). Br. Med. Bull. 29, 172–178 (1973).

    Google Scholar 

  61. Surmeier, D. J., Eberwine, J., Wilson, C. J., Stefani, A. & Kitai, S. T. Dopamine receptor subtypes co-localize in rat striatonigral neurons. Proc. Natl Acad. Sci. USA 89, 10178–10182 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Surmeier, D. J., Reiner, A., Levine, M. S. & Ariano, A. Are neostriatal dopamine receptors co-localized? Trends Neurosci. 16, 299–305 (1993).

    CAS  PubMed  Google Scholar 

  63. Schiffmann, S. N., Lledo, P. M. & Vincent, J. D. Dopamine D1 receptor modulates the voltage-gated sodium current in rat striatal neurons through a protein kinase A. J. Physiol. 483, 95–107 (1995).Electrophysiological experiments indicating functional modulation of brain sodium channels in striatal neurons by dopamine acting through PKA.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Cepeda, C., Chandler, S. H., Shumate, L. W. & Levine, M. S. Persistent Na+ conductance in medium-sized neostriatal neurons: characterization using infrared videomicroscopy and whole cell patch-clamp recordings. J. Neurophysiol. 74, 1343–1348 (1995).

    CAS  PubMed  Google Scholar 

  65. Schiffmann, S. N. et al. Modulation of the voltage-gated sodium current in rat striatal neurons by DARPP-32, an inhibitor of protein phosphatase. Eur. J. Neurosci. 10, 1312–1320 (1998).

    CAS  PubMed  Google Scholar 

  66. Aizman, O. et al. Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons. Nature Neurosci. 3, 226–230 (2000).

    CAS  PubMed  Google Scholar 

  67. Mittmann, T. & Alzheimer, C. Muscarinic inhibition of persistent Na+ current in rat neocortical pyramidal neurons. J. Neurophysiol. 79, 1579–1582 (1998).

    CAS  PubMed  Google Scholar 

  68. Maurice, N., Tkatch, T., Meisler, M. H., Sprunger, L. K. & Surmeier, D. J. D1/D5 dopamine receptor activation differentially modulates rapidly inactivating and persistent sodium currents in prefrontal cortex pyramidal neurons. J. Neurosci. 21, 2268–2277 (2001).Na V 1.6 sodium channels are not efficiently modulated by neurotransmitters coupled to PKA activation because they lack the S573 phosphorylation site.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Maurice, N., Tkatch, T. & Surmeier, J. D1/D5 dopamine receptor activation suppresses rapidly inactivating but not persistent sodium currents in rat prefrontal cortex pyramidal neurons. Soc. Neurosci. Abstr. 26, 1432 (2000).

  70. Gorelova, N. & Yang, C. R. Dopamine D1/D5 receptor activation modulates a persistent sodium current in rat prefrontal cortical neurons in vitro. J. Neurophysiol. 84, 75–87 (2000).

    CAS  PubMed  Google Scholar 

  71. Astman, N., Gutnick, M. J. & Fleidervish, I. A. Activation of protein kinase C increases neuronal excitability by regulating persistent Na+ current in mouse neocortical slices. J. Neurophysiol. 80, 1547–1551 (1998).

    CAS  PubMed  Google Scholar 

  72. Akopian, A. N. et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nature Neurosci. 2, 541–548 (1999).

    CAS  PubMed  Google Scholar 

  73. Cummins, T. R. et al. A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons. J. Neurosci. 19, RC43 (1999).

  74. Gold, M. S., Reichling, D. B., Shuster, M. J. & Levine, J. D. Hyperalgesic agents increase a tetrodotoxin-resistant Na + current in nociceptors. Proc. Natl Acad. Sci. USA 93, 1108–1112 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Cardenas, C. G., Del Mar, L. P., Cooper, B. Y. & Scroggs, R. S. 5HT4 receptors couple positively to tetrodotoxin-insensitive sodium channels in a subpopulation of capsaicin-sensitive rat sensory neurons. J. Neurosci. 17, 7181–7189 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. England, S., Bevan, S. & Docherty, R. J. PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade. J. Physiol. 495, 429–440 (1996).References 74 – 76 provide compelling evidence for PKA-dependent up-regulation of TTX-resistant sodium channels in sensory neurons.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Gold, M. S., Levine, J. D. & Correa, A. M. Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro. J. Neurosci. 18, 10345–10355 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Fitzgerald, E. M., Okuse, K., Wood, J. D., Dolphin, A. C. & Moss, S. J. cAMP-dependent phosphorylation of the tetrodotoxin-resistant voltage-dependent sodium channel SNS. J. Physiol. 516, 433–446 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Surmeier, D. J. & Kitai, S. T. State-dependent regulation of neuronal excitability by dopamine. Jap. J. Psychopharmacol. 17, 105–110 (1997) PubMed. Indicates that the input–output relationships of neostriatal neurons might be regulated by neurotransmitter dependent modulation of voltage-gated sodium channels.

    CAS  Google Scholar 

  80. Calabresi, P., Misgeld, U. & Dodt, H. U. Intrinsic membrane properties of neostriatal neurons can account for their low level of spontaneous activity. Neuroscience 20, 293–303 (1987).

    CAS  PubMed  Google Scholar 

  81. White, F. J. & Kalivas, P. W. Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend. 51, 141–153 (1998).

    CAS  PubMed  Google Scholar 

  82. Galloway, M. P. in Cocaine: Pharmacology, Physiology and Clinical Strategies. (eds Lakoski, J. M., Galloway, M. P. & White, F. J.) 163–189 (CRC, Boca Raton,1992).

    Google Scholar 

  83. Zhang, X., Hu, X. & White, F. J. Whole-cell plasticity in cocaine withdrawal: reduced sodium currents in nucleus accumbens neurons. J. Neurosci. 18, 488–498 (1998).Indicates an important role for sodium channel neuromodulation in mediating cocaine effects in the nucleus accumbens.

    PubMed  PubMed Central  Google Scholar 

  84. Biscoe, T. J. & Straughan, D. W. Microiontophoretic studies of neurones in the cat hippocampus. J. Physiol. 183, 341–359 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Herrling, P. L. The membrane potential of cat hippocampal neurons recorded in vivo displays four different reaction mechanisms to iontophoretically applied transmitter agonists. Brain Res. 212, 331–343 (1981).

    CAS  PubMed  Google Scholar 

  86. Stanzione, P., Calabresi, P., Mercuri, N. B. & Bernardi, G. Dopamine modulates CA1 hippocampal neurons by elevating the threshold for spike generation: an in vitro study. Neuroscience 13, 1105–1116 (1984).

    CAS  PubMed  Google Scholar 

  87. Pockett, S. Dopamine changes the shape of action potentials in hippocampal pyramidal cells. Brain Res. 342, 386–390 (1985).

    CAS  PubMed  Google Scholar 

  88. Malenka, R. C. & Nicoll, R. A. Dopamine decreases the calcium-activated afterhyperpolarization in hippocampal CA1 pyramidal cells. Brain Res. 379, 210–215 (1986).

    CAS  PubMed  Google Scholar 

  89. Berretta, N. et al. Effects of dopamine, D-1 and D-2 dopaminergic agonists on the excitability of hippocampal CA1 pyramidal cells in a guinea pig. Exp. Brain Res. 83, 124–130 (1990).

    CAS  PubMed  Google Scholar 

  90. Bernardo, L. S. & Prince, D. A. Dopamine modulates a Ca2+ activated potassium conductance in mammalian hippocampal pyramidal cells. Nature 297, 76–79 (1990).

    Google Scholar 

  91. Hass, H. L. & Konnerth, A. Histamine and noradrenaline decrease calcium-activated potassium conductance in hippocampal pyramidal cells. Nature 302, 432–434 (1983).

    Google Scholar 

  92. Frotscher, M. & Leranth, C. Cholinergic innervation of the hippocampus as revealed by choline acetyltransferase immunocytochemistry: a combined light and electron microscopic study. J. Comp. Neurol. 239, 237–246 (1985).

    CAS  PubMed  Google Scholar 

  93. McKinney, M. & Richelson, E. The coupling of the neuronal muscarinic receptor to responses. Annu. Rev. Pharmacol. Toxicol. 24, 121–146 (1984).

    CAS  PubMed  Google Scholar 

  94. Nicoll, R. A. The septo-hippocampal projection: a model cholinergic pathway. Trends Neurosci. 8, 533–536 (1985).

    CAS  Google Scholar 

  95. Krnjevic, K. Central cholinergic mechanisms and function. Prog. Brain Res. 98, 285–292 (1993).

    CAS  PubMed  Google Scholar 

  96. Price, D. L., Koliatsos, V. E. & Clatterbuck, R. C. Cholinergic systems: human diseases, animal models, and prospects for therapy. Prog. Brain Res. 98, 51–60 (1993).

    CAS  PubMed  Google Scholar 

  97. Wainer, B. H. et al. Ascending cholinergic pathways: functional organization and implications for disease models. Prog. Brain Res. 98, 9–30 (1993).

    CAS  PubMed  Google Scholar 

  98. Azouz, R., Jensen, M. S. & Yaari, Y. Muscarinic modulation of intrinsic burst firing in rat hippocampal neurons. Eur. J. Neurosci. 6, 961–966 (1994).

    CAS  PubMed  Google Scholar 

  99. Alroy, G., Su, H. & Yaari, Y. Protein kinase C mediates muscarinic block of intrinsic bursting in rat hippocampal neurons. J. Physiol. 518, 71–79 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Lisman, J. E. Bursts as a unit of neural information: making unreliable synapses reliable. Trends Neurosci. 20, 38–43 (1997).

    CAS  PubMed  Google Scholar 

  101. Metherate, R., Cox, C. L. & Ashe, J. H. Cellular bases of neocortical activation: modulation of neural oscillations by the nucleus basalis and endogenous acetylcholine. J. Neurosci. 12, 4701–4711 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Nordin, M., Nystrom, B., Wallin, U. & Hagbarth, K.-E. Ectopic sensory discharges and paresthesiae in patients with disorders of peripheral nerves, dorsal roots and dorsal columns. Pain 20, 231–245 (1984).

    CAS  PubMed  Google Scholar 

  103. Ochoa, J. & Torebjork, H. E. Paresthesiae from ectopic impulse generation in human sensory nerves. Brain 103, 835–854 (1980).

    CAS  PubMed  Google Scholar 

  104. Gold, M. S. Tetrodotoxin-resistant Na + currents and inflammatory hyperalgesia. Proc. Natl Acad. Sci. USA 96, 7645–7649 (1999).Indicates a role for PKA/PKC-dependent upregulation of TTX-resistant sodium current in mediating heightened excitability of nociceptor neurons in response to inflammatory stimuli.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Porreca, R. et al. A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proc. Natl Acad. Sci. USA 96, 7640–7644 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Waxman, S. G. & Wood, J. D. Sodium channels: from mechanisms to medicines? Brain Res. Bull. 50, 309–310 (1999).

    CAS  PubMed  Google Scholar 

  107. Walraven, J., Enroth-Cugel, C., Hood, D. C., MacLeod, D. I. A. & Schnapf, J. L. in Visual Perception: The Neurophysiological Foundations. (eds Spillman, L. & Werner, S. J.) 53–101 (Academic Press, San Diego,1990).

    Google Scholar 

  108. Koutalos, Y. & Yau, K. W. Regulation of sensitivity in vertebrate rod photoreceptors by calcium. Trends Neurosci. 19, 73–81 (1996).

    CAS  PubMed  Google Scholar 

  109. Kim, K. J. & Rieke, F. Temporal contrast adaptation in the salamander retina. Invest. Ophthalmol. Vis. Sci. 41 S937 (2000).

    Google Scholar 

  110. Hilborn, M. D., Vaillancourt, R. R. & Rane S. G. Growth factor receptor tyrosine kinases acutely regulate neuronal sodium channels through the Src signaling pathway. J. Neurosci. 18, 590–600 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Ratcliffe, C. F. et al. A sodium channel signaling complex: modulation by associated receptor protein tyrosine phosphatase β. Nature Neurosci. 3, 437–444 (2000).

    CAS  PubMed  Google Scholar 

  112. Cummins, T. R., Jiang, C. & Haddad, G. G. Human neocortical excitability is decreased during anoxia via sodium channel modulation. J. Clin. Invest. 91, 608–615 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Li, Z. et al. Nitric oxide as an autocrine regulator of sodium currents in baroreceptor neurons. Neuron 20, 1039–1049 (1998).

    CAS  PubMed  Google Scholar 

  114. Hammarstrom, A. K. & Gage, P. W. Oxygen-sensing persistent sodium channels in rat hippocampus. J. Physiol. 529, 107–118 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Hammarstrom, A. K. & Gage, P. W. Nitric oxide increases persistent sodium current in rat hippocampal neurons. J. Physiol. 520, 451–461 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Ma, J. Y., Catterall, W. A. & Scheuer, T. Persistent sodium current through brain sodium channels induced by G protein βγ subunits. Neuron 19, 443–452 (1997).

    CAS  PubMed  Google Scholar 

  117. Ma, J. Y., Li, M., Catterall, W. A. & Scheuer, T. Modulation of brain Na+ channels by a G-protein-coupled pathway. Proc. Natl Acad. Sci. USA 91, 12351–12355 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis, 38163, Tennessee, USA

    Angela R. Cantrell

  2. Department of Pharmacology, University of Washington, Box 357280, Seattle, 98195-7280, Washington, USA

    William A. Catterall

Authors
  1. Angela R. Cantrell
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Related links

Related links

DATABASE LINKS

Voltage-gated Na+ channels

PKA

PKC

calcineurin

M1

M3

M5

D1

D5

D2

D3

D4

FURTHER INFORMATION

The ion channel web page

Families of transport proteins

Glossary

CELLULAR PLASTICITY

A form of plasticity that modifies the entire output of a neuron.

SYNAPTOSOME

The presynaptic terminal isolated after subcellular fractionation. This structure retains the anatomical integrity of the terminal and can take up, store and release neurotransmitters.

PHORBOL ESTERS

Molecules capable of activating protein kinase C, probably by substituting for diacylglycerol. Phorbol esters can act as tumour promoters.

CELL-ATTACHED PATCH-CLAMP RECORDINGS

Recording configuration in which the patch of membrane at the tip of the recording electrode is not excised but remains attached to the whole cell.

STEADY-STATE INACTIVATION

The inactivation of a channel in response to prolonged changes in membrane voltage.

VERATRIDINE

Plant alkaloid that binds to Na+ channels and stabilizes them in the open state.

MEDIUM SPINY NEOSTRIATAL NEURONS

The main neuron population of the ventral and neuron dorsal striatum; these GABA projection neurons form the two main outputs of these structures, called the direct and indirect pathways.

CURRENT–VOLTAGE RELATIONSHIP

A plot of the changes in ionic current as a function of membrane voltage.

ANHEDONIA

Loss of interest or pleasure in almost all activities.

NUCLEUS BASALIS

Telencephalic nucleus. The main provider of cortical acetylcholine.

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Cantrell, A., Catterall, W. Neuromodulation of Na+ channels: An unexpected form of cellular platicity. Nat Rev Neurosci 2, 397–407 (2001). https://doi.org/10.1038/35077553

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