Molecular Neurobiology

, Volume 30, Issue 3, pp 279–305 | Cite as

Regulation of recombinant and native hyperpolarization-activated cation channels

  • Samuel G. A. Frère
  • Mira Kuisle
  • Anita Lüthi


Ionic currents generated by hyperpolarization-activated cation-nonselective (HCN) channels have been principally known as pacemaker h-currents (Ih), because they allow cardiac and neuronal cells to be rhythmically active over precise intervals of time. Presently, these currents are implicated in numerous additional cellular functions, including neuronal integration, synaptic transmission, and sensory reception. These roles are accomplished by virtue of the regulation of Ih by both voltage and ligands. The article summarizes recent developments on the properties and allosteric interactions of these two regulatory pathways in cloned and native channels. Additionally, it discusses how the expression and properties of native channels may be controlled via regulation of the transcription of the HCN channel gene family and the assembly of channel subunits. Recently, several cardiac and neurological diseases were found to be intimately associated with a dysregulation of HCN gene transcription, suggesting that HCN-mediated currents may be involved in the pathophysiology of excitable systems. As a starting point, we briefly review the general characteristics of Ih and the regulatory mechanisms identified in heterologously expressed HCN channels.

Index Entries

Pacemaker rhythmogenesis ion channel allosteric cyclic AMP phosphorylation transcriptional regulation cardiopathy epilepsy injury 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Accili E. A., Proenza C., Baruscotti M., and DiFrancesco D. (2002) From funny current to HCN channels: 20 years of excitation. News Physiol. Sci. 17, 32–37.PubMedGoogle Scholar
  2. 2.
    Biel M., Schneider A., and Wahl C. (2002) Cardiac HCN channels: structure, function, and modulation. Trends Cardiovasc. Med. 12, 206–212.PubMedCrossRefGoogle Scholar
  3. 3.
    Kaupp U. B. and Seifert R. (2001) Molecular diversity of pacemaker ion channels. Annu. Rev. Physiol. 63, 235–257.PubMedCrossRefGoogle Scholar
  4. 4.
    Robinson R. B. and Siegelbaum S. A. (2003) Hyperpolarization-activated cation currents: from molecules to physiological function. Annu. Rev. Physiol. 65, 453–480.PubMedCrossRefGoogle Scholar
  5. 5.
    Ulens C. and Tytgat J. (2001) Functional heteromerization of HCN1 and HCN2 pacemaker channels. J Biol. Chem. 276, 6069–6072.PubMedCrossRefGoogle Scholar
  6. 6.
    Yu H., Wu J., Potapova I., et al. (2001) MinKrelated peptide 1: a β subunit for the HCN ion channel subunit family enhances expression and speeds activation. Circ. Res. 88, E84-E87.PubMedGoogle Scholar
  7. 7.
    Altomare C., Terragni B., Brioschi C., et al. (2003) Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node. J. Physiol. 549, 347–359.PubMedCrossRefGoogle Scholar
  8. 8.
    Decher N., Bundis F., Vajna R., and Steinmeyer K. (2003) KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents. Pflügers Arch. 446, 633–640.PubMedCrossRefGoogle Scholar
  9. 9.
    Much B., Wahl-Schott C., Zong X., et al. (2003) Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotidegated channels. J. Biol. Chem. 278, 43,781–43,786.CrossRefGoogle Scholar
  10. 10.
    Santoro B. and Baram T. Z. (2003) The multiple personalities of h-channels. Trends Neurosci. 26, 550–554.PubMedCrossRefGoogle Scholar
  11. 11.
    Brown H. F., DiFrancesco D., and Noble S. J. (1979) How does adrenaline accelerate the heart? Nature 280, 235, 236.PubMedCrossRefGoogle Scholar
  12. 12.
    Halliwell J. V. and Adams P. R. (1982) Voltageclamp analysis of muscarinic excitation in hippocampal neurons. Brain Res. 250, 71–92.PubMedCrossRefGoogle Scholar
  13. 13.
    Knopfel T., Guatteo E., Bernardi G., and Mercuri N. B. (1998) Hyperpolarization induces a rise in intracellular sodium concentration in dopamine cells of the substantia nigra pars compacta. Eur. J. Neurosci. 10, 1926–1929.PubMedCrossRefGoogle Scholar
  14. 14.
    Yu X., Duan K. L., Shang C. F., Yu H. G., and Zhou Z. (2004) Calcium influx through hyperpolarization-activated cation channels (Ih channels) contributes to activity-evoked neuronal secretion. Proc. Natl. Acad. Sci. USA 101, 1051–1056.PubMedCrossRefGoogle Scholar
  15. 15.
    Ray A. M., Benham C. D., Roberts J. C., et al. (2003) Capsazepine protects against neuronal injury caused by oxygen glucose deprivation by inhibiting Ih. J. Neurosci. 23, 10,146–10,153.Google Scholar
  16. 15a.
    Gill C. H., Randall A., Bates S. A., et al. (2004) Characterization of the human HCN1 channel and its inhibition by capsazepine. Br. J. Pharmacol. 143, 411–421.PubMedCrossRefGoogle Scholar
  17. 16.
    Perkins K. L. and Wong R. K. (1995) Intracellular QX-314 blocks the hyperpolarizationactivated inward current Iq in hippocampal CA1 pyramidal cells. J. Neurophysiol. 73, 911–915.PubMedGoogle Scholar
  18. 17.
    Pape H. C. (1994) Specific bradycardiac agents block the hyperpolarization-activated cation current in central neurons. Neuroscience 59, 363–373.PubMedCrossRefGoogle Scholar
  19. 18.
    Harris N. C. and Constanti A. (1995) Mechanism of block by ZD 7288 of the hyperpolarization-activated inward rectifying current in guinea pig substantia nigra neurons in vitro. J. Neurophysiol. 74, 2366–2378.PubMedGoogle Scholar
  20. 19.
    Chevaleyre V. and Castillo P. E. (2002) Assessing the role of Ih channels in synaptic transmission and mossy fiber LTP. Proc. Natl. Acad. Sci. USA 99, 9538–9543.PubMedCrossRefGoogle Scholar
  21. 20.
    Constanti A. and Galvan M. (1983) Fast inward-rectifying current accounts for anomalous rectification in olfactory cortex neurons. J. Physiol. 335, 153–178.PubMedGoogle Scholar
  22. 21.
    Janigro D., Gasparini S., D’Ambrosio R., McKhann G. II, and DiFrancesco D. (1997) Reduction of K+ uptake in glia prevents long-term depression maintenance and causes epileptiform activity. J. Neurosci. 17, 2813–2824.PubMedGoogle Scholar
  23. 22.
    Uchimura N., Cherubini E., and North R. A. (1990) Cation current activated by hyperpolarization in a subset of rat nucleus accumbens neurons. J. Neurophysiol. 64, 1847–1850.PubMedGoogle Scholar
  24. 23.
    Womble M. D. and Moises H. C. (1993) Hyperpolarization-activated currents in neurons of the rat basolateral amygdala. J. Neurophysiol. 70, 2056–2065.PubMedGoogle Scholar
  25. 24.
    Akasu T. and Shoji S. (1994) cAMP-dependent inward rectifier current in neurons of the rat suprachiasmatic nucleus. Pflügers Arch. 429, 117–125.PubMedCrossRefGoogle Scholar
  26. 25.
    Doan T. N. and Kunze D. L. (1999) Contribution of the hyperpolarization-activated current to the resting membrane potential of rat nodose sensory neurons. J. Physiol. 514, 125–138.PubMedCrossRefGoogle Scholar
  27. 26.
    Santoro B. and Tibbs G. R. (1999) The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels. Ann. NY Acad. Sci. 868, 741–764.PubMedCrossRefGoogle Scholar
  28. 27.
    Araki T., Ito M., and Oshima T. (1961) Potential changes produced by application of current steps in motoneurones. Nature 191, 1104, 1105.PubMedCrossRefGoogle Scholar
  29. 28.
    Ito M. and Oshima T. (1965) Electrical behaviour of the motoneurone membrane during intracellularly applied current steps. J. Physiol. 180, 607–635.PubMedGoogle Scholar
  30. 29.
    Fain G. L., Quandt F. N., Bastian B. L., and Gerschenfeld H. M. (1978) Contribution of a caesium-sensitive conductance increase to the rod photoresponse. Nature 272, 466–469.PubMedCrossRefGoogle Scholar
  31. 30.
    Bader C. R. and Bertrand D. (1984) Effect of changes in intra- and extracellular sodium on the inward (anomalous) rectification in salamander photoreceptors. J. Physiol. 347, 611–631.PubMedGoogle Scholar
  32. 31.
    Bader C. R., Macleish P. R., and Schwartz E. A. (1979) A voltage-clamp study of the light response in solitary rods of the tiger salamander. J. Physiol. 296, 1–26.PubMedGoogle Scholar
  33. 32.
    DiFrancesco D. (1985) The cardiac hyperpolarizing-activated current, if. Origins and developments. Prog. Biophys. Mol. Biol. 46, 163–183.PubMedCrossRefGoogle Scholar
  34. 33.
    Zaza A., Micheletti M., Brioschi A., and Rocchetti M. (1997) Ionic currents during sustained pacemaker activity in rabbit sino-atrial myocytes. J. Physiol. 505, 677–688.PubMedCrossRefGoogle Scholar
  35. 34.
    Maier S. K., Westenbroek R. E., Yamanushi T. T., et al. (2003) An unexpected requirement for brain-type sodium channels for control of heart rate in the mouse sinoatrial node. Proc. Natl. Acad. Sci. USA 11, 3507–3512.CrossRefGoogle Scholar
  36. 35.
    Schram G., Pourrier M., Melnyk P., and Nattel S. (2002) Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function. Circ. Res. 90, 939–950.PubMedCrossRefGoogle Scholar
  37. 36.
    Ludwig A., Budde T., Stieber J., et al. (2003) Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J. 22, 216–224.PubMedCrossRefGoogle Scholar
  38. 37.
    Stieber J., Herrmann S., Feil S., et al. (2003) The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc. Natl. Acad. Sci. USA 100, 15,235–15,240.CrossRefGoogle Scholar
  39. 38.
    Er F., Larbig R., Ludwig A., et al. (2003) Dominant-negative suppression of HCN channels markedly reduces the native pacemaker current If and undermines spontaneous beating of neonatal cardiomyocytes. Circulation 107, 485–489.PubMedCrossRefGoogle Scholar
  40. 39.
    Baker K., Warren K. S., Yellen G., and Fishman M. C. (1997) Defective ‘pacemaker’ current (Ih) in a zebrafish mutant with a slow heart rate. Proc. Natl. Acad. Sci. USA 94, 4554–4559.PubMedCrossRefGoogle Scholar
  41. 40.
    Warren K. S., Baker K., and Fishman M. C. (2001) The slow mo mutation reduces pacemaker current and heart rate in adult zebrafish. Am. J. Physiol. Heart. Circ. Physiol. 281, H1711-H1719.PubMedGoogle Scholar
  42. 41.
    Satoh H. (1995) Identification of a hyperpolarization-activated inward current in uterine smooth muscle cells during pregnancy. Gen. Pharmacol. 26, 1335–1338.PubMedGoogle Scholar
  43. 42.
    Galligan J. J., Tatsumi H., Shen K. Z., Surprenant A., and North R. A. (1990) Cation current activated by hyperpolarization (Ih) in guinea pig enteric neurons. Am. J. Physiol. 259, G966-G972.PubMedGoogle Scholar
  44. 43.
    Solomon J. S., Doyle J. F., Burkhalter A., and Nerbonne J. M. (1993) Differential expression of hyperpolarization-activated currents reveals distinct classes of visual cortical projection neurons. J. Neurosci. 13, 5082–5091.PubMedGoogle Scholar
  45. 44.
    McCormick D. A. and Pape H. C. (1990) Properties of a hyperpolarization-activated cation current and its role in rhythmic oscillation in thalamic relay neurones. J. Physiol. 431, 291–318.PubMedGoogle Scholar
  46. 45.
    Bal T. and McCormick D. A. (1996) What stops synchronized thalamocortical oscillations? Neuron 17, 297–308.PubMedCrossRefGoogle Scholar
  47. 46.
    Luthi A. and McCormick D. A. (1998) H-current: properties of a neuronal and network pacemaker. Neuron 21, 9–12.PubMedCrossRefGoogle Scholar
  48. 47.
    Fisahn A., Yamada M., Duttaroy A., et al. (2002) Muscarinic induction of hippocampal gamma oscillations requires coupling of the M1 receptor to two mixed cation currents. Neuron 33, 615–624.PubMedCrossRefGoogle Scholar
  49. 48.
    Bal T. and McCormick D. A. (1997) Synchronized oscillations in the inferior olive are controlled by the hyperpolarization-activated cation current Ih. J. Neurophysiol. 77, 3145–3156.PubMedGoogle Scholar
  50. 49.
    Dickson C. T., Magistretti J., Shalinsky M. H., Fransen E., Hasselmo M. E., and Alonso A. (2000) Properties and role of Ih in the pacing of subthreshold oscillations in entorhinal cortex layer II neurons. J. Neurophysiol. 83, 2562–2579.PubMedGoogle Scholar
  51. 50.
    Maccaferri G. and McBain C. J. (1996) The hyperpolarization-activated current (Ih) and its contribution to pacemaker activity in rat CA1 hippocampal stratum oriens-alveus interneurones. J. Physiol. 497, 119–130.PubMedGoogle Scholar
  52. 51.
    Bennett B. D., Callaway J. C., and Wilson C. J. (2000) Intrinsic membrane properties underlying spontaneous tonic firing in neostriatal cholinergic interneurons. J. Neurosci. 20, 8493–8503.PubMedGoogle Scholar
  53. 52.
    Neuhoff H., Neu A., Liss B., and Roeper J. (2002) Ih channels contribute to the different functional properties of identified dopaminergic subpopulations in the midbrain. J. Neurosci. 22, 1290–1302.PubMedGoogle Scholar
  54. 53.
    Funahashi M., Mitoh Y., Kohjitani A., and Matsuo R. (2003) Role of the hyperpolarization-activated cation current (Ih) in pacemaker activity in area postrema neurons of rat brain slices. J. Physiol. 552, 135–148.PubMedCrossRefGoogle Scholar
  55. 54.
    Thoby-Brisson M., Telgkamp P., and Ramirez J. M. (2000) The role of the hyperpolarization-activated current in modulating rhythmic activity in the isolated respiratory network of mice. J. Neurosci. 20, 2994–3005.PubMedGoogle Scholar
  56. 55.
    Ghamari-Langroudi M. and Bourque C. W. (2000) Excitatory role of the hyperpolarization-activated inward current in phasic and tonic firing of rat supraoptic neurons. J. Neurosci. 20, 4855–4863.PubMedGoogle Scholar
  57. 56.
    Agmon A. and Wells J. E. (2003) The role of the hyperpolarization-activated cationic current Ih in the timing of interictal bursts in the neonatal hippocampus. J. Neurosci. 23, 3658–3668.PubMedGoogle Scholar
  58. 57.
    Magee J. C. (1999) Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons. Nat. Neurosci. 2, 508–514.PubMedCrossRefGoogle Scholar
  59. 58.
    Williams S. R. and Stuart G. J. (2000) Site independence of EPSP time course is mediated by dendritic Ih in neocortical pyramidal neurons. J. Neurophysiol. 83, 3177–3182.PubMedGoogle Scholar
  60. 59.
    Berger T., Larkum M. E., and Lüscher H. R. (2001) High Ih channel density in the distal apical dendrite of layer V pyramidal cells increases bidirectional attenuation of EPSPs. J. Neurophysiol. 85, 855–868.PubMedGoogle Scholar
  61. 60.
    Lörincz A., Notomi T., Tamas G., Shigemoto R., and Nusser Z. (2002) Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites. Nat. Neurosci. 5, 1185–1193.PubMedCrossRefGoogle Scholar
  62. 61.
    Magee J. C. (2000) Dendritic integration of excitatory synaptic input. Nat. Neurosci. 1, 181–190.CrossRefGoogle Scholar
  63. 62.
    Desjardins A. E., Li Y. X., Reinker S., Miura R. M., and Neuman R. S. (2003) The influences of Ih on temporal summation in hippocampal CA1 pyramidal neurons: a modeling study. J. Comp. Neurosci. 15, 131–142.CrossRefGoogle Scholar
  64. 63.
    Williams S. R., Christensen S. R., Stuart G. J., and Hausser M. (2002) Membrane potential bistability is controlled by the hyperpolarization-activated current IH in rat cerebellar Purkinje neurons in vitro. J. Physiol. 539, 469–483.PubMedCrossRefGoogle Scholar
  65. 64.
    Nolan M. F., Malleret G., Lee K. H., et al. (2003) The hyperpolarization-activated HCN1 channel is important for motor learning and neuronal integration by cerebellar Purkinje cells. Cell 115, 551–564.PubMedCrossRefGoogle Scholar
  66. 65.
    Ulrich D. (2002) Dendritic resonance in rat neocortical pyramidal cells. J. Neurophysiol. 87, 2753–2759.PubMedGoogle Scholar
  67. 66.
    Magee J. C. (2001) Dendritic mechanisms of phase precession in hippocampal CA1 pyramidal neurons. J. Neurophysiol. 86, 528–532.PubMedGoogle Scholar
  68. 67.
    Santoro B., Grant S. G., Bartsch D., and Kandel E. R. (1997) Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels. Proc. Natl. Acad. Sci. USA 94, 14,815–14,820.Google Scholar
  69. 68.
    Müller F., Scholten A., Ivanova E., Haverkamp S., Kremmer E., and Kaupp U. B. (2003) HCN channels are expressed differentially in retinal bipolar cells and concentrated at synaptic terminals. Eur. J. Neurosci. 17, 2084–2096.PubMedCrossRefGoogle Scholar
  70. 69.
    Southan A. P., Morris N. P., Stephens G. J., and Robertson B. (2000) Hyperpolarization-activated currents in presynaptic terminals of mouse cerebellar basket cells. J. Physiol. 526, 91–97.PubMedCrossRefGoogle Scholar
  71. 70.
    Cuttle M. F., Rusznak Z., Wong A. Y., Owens S., and Forsythe I. D. (2001) Modulation of a presynaptic hyperpolarization-activated cationic current (Ih) at an excitatory synaptic terminal in the rat auditory brainstem. J. Physiol. 534, 733–744.PubMedCrossRefGoogle Scholar
  72. 71.
    Mellor J., Nicoll R. A., and Schmitz D. (2002) Mediation of hippocampal mossy fiber long-term potentiation by presynaptic Ih channels. Science 295, 143–147.PubMedCrossRefGoogle Scholar
  73. 72.
    Beaumont V. and Zucker R. S. (2000) Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih channels. Nat. Neurosci. 3, 133–141.PubMedCrossRefGoogle Scholar
  74. 73.
    Beaumont V., Zhong N., Froemke R. C., Ball R. W., and Zucker R. S. (2002) Temporal synaptic tagging by Ih activation and actin: involvement in long-term facilitation and cAMP-induced synaptic enhancement. Neuron 33, 601–613.PubMedCrossRefGoogle Scholar
  75. 74.
    Stevens D. R., Seifert R., Bufe B., et al. (2001) Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli. Nature 413, 631–635.PubMedCrossRefGoogle Scholar
  76. 75.
    Viana F., de la Pena E., and Belmonte C. (2002) Specificity of cold thermotransduction is determined by differential ionic channel expression. Nat. Neurosci. 5, 254–260.PubMedCrossRefGoogle Scholar
  77. 76.
    Gauss R., Seifert R., and Kaupp U. B. (1998) Molecular identification of a hyperpolarization-activated channel in sea urchin sperm. Nature 393, 583–587.PubMedCrossRefGoogle Scholar
  78. 77.
    Ludwig A., Zong X., Jeglitsch M., Hofmann F., and Biel M. (1998) A family of hyperpolarization-activated mammalian cation channels. Nature 393, 587–591.PubMedCrossRefGoogle Scholar
  79. 78.
    Santoro B., Liu D. T., Yao H., et al. (1998) Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell 93, 717–729.PubMedCrossRefGoogle Scholar
  80. 79.
    Clapham D. E. (1998) Not so funny anymore: pacing channels are cloned. Neuron 21, 5–7.PubMedCrossRefGoogle Scholar
  81. 80.
    Doyle D. A., Morais Cabral J., Pfuetzner R. A., et al. (1998) The structure of the potassium channels: molecular basis of K+ conduction and selectivity. Science 280, 69–77.PubMedCrossRefGoogle Scholar
  82. 81.
    Gauss R. and Seifert R. (2000) Pacemaker oscillations in heart and brain: a key role for hyperpolarization-activated cation channels. Chronbiol. Internat. 17, 453–469.CrossRefGoogle Scholar
  83. 82.
    Proenza C., Angoli D., Agranovich E., Macri V., and Accili E. A. (2002) Pacemaker channels produce an instantaneous current. J. Biol. Chem. 277, 5101–5109.PubMedCrossRefGoogle Scholar
  84. 83.
    Macri V. S. and Accili E. A. (2004) Structural elements of instantaneous and slow gating in HCN channels. J. Biol. Chem. 279, 16,832–16,846.CrossRefGoogle Scholar
  85. 84.
    Moosmang S., Biel M., Hofmann F., and Ludwig A. (1999) Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Biol. Chem. 380, 975–980.PubMedCrossRefGoogle Scholar
  86. 85.
    Franz O., Liss B., Neu A., and Roeper J. (2000) Single-cell mRNA expression of HCN1 correlates with a fast gating phenotype of hyperpolarization-activated cyclic nucleotide-gated ion channels (Ih) in central neurons. Eur. J. Neurosci. 12, 2685–2693.PubMedCrossRefGoogle Scholar
  87. 86.
    Monteggia L. M., Eisch A. J., Tang M. D., Kaczmarek L. K., and Nestler E. J. (2000) Cloning and localization of the hyperpolarization-activated cyclic nucleotide-gated channel family in rat brain. Brain Res. Mol. Brain Res. 81, 129–139.PubMedCrossRefGoogle Scholar
  88. 87.
    Santoro B., Chan S., Lüthi A., et al. (2000) Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS. J. Neurosci. 20, 5264–5275.PubMedGoogle Scholar
  89. 88.
    Chen S., Wang J., and Siegelbaum S. A. (2001) Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. J. Gen. Physiol. 117, 491–504.PubMedCrossRefGoogle Scholar
  90. 89.
    Abbott G. W., Goldstein S. A., and Sesti F. (2001) Do all voltage-gated potassium channels use MiRPs? Circ. Res. 88, 981–983.PubMedGoogle Scholar
  91. 90.
    Wainger B. J., DeGennaro M., Santoro B., Siegelbaum S. A., and Tibbs G. R. (2001) Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature 411, 805–810.PubMedCrossRefGoogle Scholar
  92. 91.
    Ulens C. and Siegelbaum S. A. (2003) Regulation of hyperpolarization-activated HCN channels by cAMP through a gating switch in binding domain symmetry. Neuron 40, 959–970.PubMedCrossRefGoogle Scholar
  93. 92.
    Barbuti A., Baruscotti M., Altomare C., Moroni A., and DiFrancesco D. (1999) Action of internal pronase on the f-channel kinetics in the rabbit SA node. J. Physiol. 520, 737–744.PubMedCrossRefGoogle Scholar
  94. 93.
    DiFrancesco D. (1999) Dual allosteric modulation of pacemaker (f) channels by cAMP and voltage in rabbit SA node. J. Physiol. 515, 367–376.PubMedCrossRefGoogle Scholar
  95. 94.
    Wang J., Chen S., and Siegelbaum S. A. (2001) Regulation of the hyperpolarization-activated HCN channel gating and cAMP modulation due to interactions of COOH terminus and core transmembrane regions. J. Gen. Physiol. 118, 237–250.PubMedCrossRefGoogle Scholar
  96. 95.
    Wang J., Chen S., Nolan M. F., and Siegelbaum S. A. (2002) Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: signaling through dynamic allosteric coupling. Neuron 36, 451–461.PubMedCrossRefGoogle Scholar
  97. 96.
    Zong X., Stieber J., Ludwig A., Hofmann F., and Biel M. (2001) A single histidine residue determines the pH sensitivity of the pacemaker channel HCN2. J. Biol. Chem. 276, 6313–6319.PubMedCrossRefGoogle Scholar
  98. 97.
    Magoski N. S., Wilson G. F., and Kaczmarek L. K. (2002) Protein kinase modulation of a neuronal cation channel requires protein-protein interactions mediated by an Src homology 3 domain. J. Neurosci. 22, 1–9.PubMedGoogle Scholar
  99. 98.
    Holmes T. C., Fadool D. A., Ren R., and Levitan I. B. (1996) Association of Src tyrosine kinase with a human potassium channel mediated by SH3 domain. Science 274, 2089–2091.PubMedCrossRefGoogle Scholar
  100. 99.
    Proenza C. and Accili E. A. (2001) Modulation of mHCN2 by cAMP. Biophys. J. 80, 208a.Google Scholar
  101. 100.
    Yu H. G., Lu Z., Pan Z., and Cohen I. S. (2003) Tyrosine kinase inhibition differentially regulates heterologously expressed HCN channels. Pflügers Arch 447, 392–400.PubMedCrossRefGoogle Scholar
  102. 101.
    Kaupp U. B. and Seifert R. (2002) Cyclic nucleotide-gated ion channels. Physiol. Rev. 82, 769–824.PubMedGoogle Scholar
  103. 102.
    Ko G. Y., Ko M. L., and Dryer S. E. (2001) Circadian regulation of cGMP-gated cationic channels of chick retinal cones. Erk MAP Kinase and Ca2+/calmodulin-dependent protein kinase II. Neuron 29, 255–266.PubMedCrossRefGoogle Scholar
  104. 103.
    Brooker G. (1973) Oscillation of cyclic adenosine monophosphate concentration during the myocardial contraction cycle. Science 182, 933–934.PubMedCrossRefGoogle Scholar
  105. 104.
    Hartzell H. C. (1988) Regulation of cardiac ion channels by catecholamines, acetylcholine and second messenger systems. Prog. Biophys. Mol. Biol. 52, 165–247.PubMedCrossRefGoogle Scholar
  106. 105.
    DiFrancesco D. and Tortora P. (1991) Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 351, 145–147.PubMedCrossRefGoogle Scholar
  107. 106.
    Pedarzani P. and Storm J. F. (1995) Protein kinase A-independent modulation of ion channels in the brain by cyclic AMP. Proc. Natl. Acad. Sci. USA 92, 11,716–11,720.CrossRefGoogle Scholar
  108. 107.
    McCormick D. A. and Pape H. C. (1990) Noradrenergic and serotonergic modulation of a hyperpolarization-activated cation current in thalamic relay neurones. J. Physiol. 431, 319–342.PubMedGoogle Scholar
  109. 108.
    Pape H. C. (1992) Adenosine promotes burst activity in guinea-pig geniculocortical neurones through two different ionic mechanisms. J. Physiol. 447, 729–753.PubMedGoogle Scholar
  110. 109.
    Frère S. G. A. and Lüthi A. (2004) Pacemaker channels in mouse thalamocortical neurons are regulated by distinct pathways of cAMP synthesis. J. Physiol. 554, 111–125.PubMedCrossRefGoogle Scholar
  111. 110.
    Bobker D. H. and Williams J. T. (1989) Serotonin augments the cationic current Ih in central neurons. Neuron 2, 1535–1540.PubMedCrossRefGoogle Scholar
  112. 111.
    Larkman P. M., Kelly J. S., and Takahashi T. (1995) Adenosine 3′:5′-cyclic monophosphate mediates a 5-hydroxytryptamine-induced response in neonatal rat motoneurones. Pflügers Arch. 430, 763–769.PubMedCrossRefGoogle Scholar
  113. 112.
    Larkman P. M. and Kelly J. S. (1997) Modulation of IH by 5-HT in neonatal rat motoneurones in vitro: mediation through a phosphorylation independent action of cAMP. Neuropharmacology 36, 721–733.PubMedCrossRefGoogle Scholar
  114. 113.
    Sun Q. Q., Prince D. A., and Huguenard J. R. (2003) Vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide activate hyperpolarization-activated cationic current and depolarize thalamocortical neurons in vitro. J. Neurosci. 23, 2751–2758.PubMedGoogle Scholar
  115. 114.
    Lee S. H. and Cox C. L. (2003) Vasoactive intestinal peptide selectively depolarizes thalamic relay neurons and attenuates intrathalamic rhythmic activity. J. Neurophysiol. 90, 1224–1234.PubMedCrossRefGoogle Scholar
  116. 115.
    Jafri M. S. and Weinreich D. (1998) Substance P regulates Ih via a NK-1 receptor in vagal sensory neurons of the ferret. J. Neurophysiol. 79, 769–777.PubMedGoogle Scholar
  117. 116.
    Ingram S. L. and Williams J. T. (1996) Modulation of the hyperpolarization-activated current (Ih) by cyclic nucleotides in guinea-pig primary afferent neurons. J. Physiol. 492, 97–106.PubMedGoogle Scholar
  118. 117.
    Ingram S. L. and Williams J. T. (1993) Opioid inhibition of Ih via adenylyl cyclase. Neuron 13, 179–186.CrossRefGoogle Scholar
  119. 118.
    Rainnie D. G., Grunze H. C., McCarley R. W., and Greene R. W. (1994) Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal. Science 263, 689–692.PubMedCrossRefGoogle Scholar
  120. 119.
    Lüthi A. and McCormick D. A. (1999) Modulation of a pacemaker current through Ca2+-induced stimulation of cAMP production. Nat. Neurosci. 2, 634–641.PubMedCrossRefGoogle Scholar
  121. 120.
    Pape H. C. and Mager R. (1992) Nitric oxide controls oscillatory activity in thalamocortical neurons. Neuron 9, 441–448.PubMedCrossRefGoogle Scholar
  122. 121.
    Hanoune J. and Defer N. (2001) Regulation and role of adenylyl cyclase isoforms. Annu. Rev. Pharmacol. Toxicol. 41, 145–174.PubMedCrossRefGoogle Scholar
  123. 122.
    Cooper D. M. (2003) Regulation and organization of adenylyl cyclases and cAMP. Biochem. J. 375, 517–529.PubMedCrossRefGoogle Scholar
  124. 123.
    Matsuoka I., Suzuki Y., Defer N., Nakanishi H., and Hanoune J. (1997) Differential expression of type I, II and V adenylyl cyclase gene in the postnatal developing rat brain. J. Neurochem. 68, 498–506.PubMedCrossRefGoogle Scholar
  125. 124.
    Ihnatovych I., Novotny J., Haugvicova R., Bourova L., Mares P., and Svoboda P. (2002) Ontogenetic development of the G protein-mediated adenylyl cyclase signalling in rat brain. Dev. Brain Res. 133, 69–75.CrossRefGoogle Scholar
  126. 125.
    Cali J. J., Zwaagstra J. C., Mons N., Cooper D. M., and Krupinski J. (1994) Type VIII adenylyl cyclase. A Ca2+/calmodulin-stimulated enzyme expressed in discrete regions of rat brain. J. Biol. Chem. 269, 12,190–12,195.Google Scholar
  127. 126.
    Sah P. and Davies P. (2000) Calcium-activated potassium currents in mammalian neurons. Clin. Exp. Pharmacol. Physiol. 27, 657–663.PubMedCrossRefGoogle Scholar
  128. 127.
    Marx S. O., Kurokawa J., Reiken S., et al. (2002) Requirement of a macromolecular signaling complex for β-adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 295, 496–499.PubMedCrossRefGoogle Scholar
  129. 128.
    Van Welie I., Van Hoofts J. A., and Wadman W. J. (2002) Rapid modulation of somatic hyperpolarization-activated inward currents by synaptic activity. Soc. Neurosci. Abstr. 344.1.Google Scholar
  130. 129.
    Strata F., Atzori M., Molnar M., Ugolini G., Tempia F., and Cherubini E. (1997) A pacemaker current in dye-coupled hilar interneurons contributes to the generation of giant GABAergic potentials in developing hippocampus. J. Neurosci. 17, 1435–1446.PubMedGoogle Scholar
  131. 130.
    McCormick D. A. and Bal T. (1997) Sleep and arousal: thalamocortical mechanisms. Annu. Rev. Neurosci. 20, 185–215.PubMedCrossRefGoogle Scholar
  132. 131.
    Lüthi A. and McCormick D. A. (1998) Periodicity of thalamic synchronized oscillations: the role of Ca2+-mediated upregulation of Ih. Neuron 20, 553–563.PubMedCrossRefGoogle Scholar
  133. 132.
    Tokimasa T. and Akasu T. (1990) Cyclic AMP regulates an inward rectifying sodium-potassium current in dissociated bullfrog sympathetic neurons. J. Physiol. 420, 409–429.PubMedGoogle Scholar
  134. 133.
    Chang F., Cohen I. S., DiFrancesco D., Rosen M. R., and Tromba C. (1991) Effects of protein kinase inhibitors on canine Purkinje fibre pacemaker depolarization and the pacemaker current if. J. Physiol. 440, 367–384.PubMedGoogle Scholar
  135. 134.
    Yu H., Chang F., and Cohen I. S. (1993) Phosphatase inhibition by calyculin A increases if in canine Purkinje fibers and myocytes. Pflügers Arch. 422, 614–616.PubMedCrossRefGoogle Scholar
  136. 135.
    Accili E. A., Redaelli G., and DiFrancesco D. (1997) Differential control of the hyperpolarization-activated current (if) by cAMP gating and phosphatase inhibition in rabbit sinoatrial node myocytes. J. Physiol. 500, 643–651.PubMedGoogle Scholar
  137. 136.
    Raes A., Wang Z., van den Berg R. J., Goethals M., Van de Vijver G., and van Bogaert P. P. (1997) Effect of cAMP and ATP on the hyperpolarization-activated current in mouse dorsal root ganglion neurons. Pflügers Arch. 434, 543–550.PubMedCrossRefGoogle Scholar
  138. 137.
    Vargas G. and Lucero M. T. (2003) Modulation by PKA of the hyperpolarization-activated current (Ih) in cultured rat olfactory receptor neurons. J. Membr. Biol. 188, 115–125.CrossRefGoogle Scholar
  139. 138.
    Levitan I. B. (1999) Modulation of ion channels by protein phosphorylation. How the brain works. Adv. Second Messenger Phosphoprotein Res. 33, 3–22.PubMedGoogle Scholar
  140. 139.
    Kramer R. H. and Molokanova E. (2001) Modulation of cyclic-nucleotide-gated channels and regulation of vertebrate phototransduction. J. Exp. Biol. 204, 2921–2931.PubMedGoogle Scholar
  141. 140.
    DiFrancesco D. and Mangoni M. (1994) Modulation of single hyperpolarization-activated channels (if) by cAMP in the rabbit sino-atrial node. J. Physiol. 474, 473–482.PubMedGoogle Scholar
  142. 141.
    Wu J. Y. and Cohen I. S. (1997) Tyrosine kinase inhibition reduces if in rabbit sinoatrial node myocytes. Pflügers Arch. 434, 509–514.PubMedCrossRefGoogle Scholar
  143. 142.
    Shibata S., Ono K., and Iijima T. (1999) Inhibition by genistein of the hyperpolarization-activated cation current in porcine sino-atrial node cells. Br. J. Pharmacol. 128, 1284–1290.PubMedCrossRefGoogle Scholar
  144. 143.
    Thoby-Brisson M., Cauli B., Champagnat J., Fortin G., and Katz D. M. (2003) Expression of functional tyrosine kinase B receptors by rhythmically active respiratory neurons in the pre-Bötzinger complex of neonatal mice. J. Neurosci. 23, 7685–7689.PubMedGoogle Scholar
  145. 144.
    Cathala L. and Paupardin-Tritsch D. (1997) Neurotensin inhibition of the hyperpolarization-activated cation current (Ih) in the rat substantia nigra pars compacta implicates the protein kinase C pathway. J. Physiol. 503, 87–97.PubMedCrossRefGoogle Scholar
  146. 145.
    Silver I. A. and Erecinska M. (1992) Ion homeostasis in rat brain in vivo: intra- and extracellular [Ca2+] and [H+] in the hippocampus during recovery from short-term, transient ischemia. J. Cereb. Blood Flow Metab. 12, 759–772.PubMedGoogle Scholar
  147. 146.
    Munsch T. and Pape H. C. (1999) Modulation of the hyperpolarization-activated cation current of rat thalamic relay neurones by intracellular pH. J. Physiol. 519, 493–504.PubMedCrossRefGoogle Scholar
  148. 147.
    Munsch T. and Pape H. C. (1999) Upregulation of the hyperpolarization-activated cation current in rat thalamic relay neurones by acetazolamide. J. Physiol. 519, 505–514.PubMedCrossRefGoogle Scholar
  149. 148.
    Yasui K., Liu W., Opthof T., et al. (2001) If current and spontaneous activity in mouse embryonic ventricular myocytes. Circ. Res. 88, 536–542.PubMedGoogle Scholar
  150. 149.
    Shi W., Wymore R., Yu H., et al. (1999) Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ. Res. 85, e1-e6.PubMedGoogle Scholar
  151. 150.
    Vasilyev D. V. and Barish M. E. (2002) Postnatal development of the hyperpolarization-activated excitatory current Ih in mouse hippocampal pyramidal neurons. J. Neurosci. 22, 8992–9004.PubMedGoogle Scholar
  152. 151.
    Bender R. A., Brewster A., Santoro B., et al. (2001) Differential and age-dependent expression of hyperpolarization-activated, cyclic nucleotide-gated cation channel isoforms 1–4 suggests evolving roles in the developing rat hippocampus. Neuroscience 106, 689–698.PubMedCrossRefGoogle Scholar
  153. 152.
    Tomaselli G. and Marban E. (1999) Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc. Res. 42, 270–283.PubMedCrossRefGoogle Scholar
  154. 153.
    Armoundas A. A., Wu R., Juang G., Marban E., and Tomaselli G. F. (2001) Electrical and structural remodeling of the failing ventricle. Pharmacol & Therapeutics 92, 213–230.CrossRefGoogle Scholar
  155. 154.
    Cerbai E., Barbieri M., and Mugelli A. (1994) Characterization of the hyperpolarization-activated current, If, in ventricular myocytes isolated from hypertensive rats. J. Physiol. 481, 585–591.PubMedGoogle Scholar
  156. 155.
    Cerbai E., Pino R., Porciatti F., et al. (1997) Characterization of the hyperpolarization-activated current, If, in ventricular myocytes from failing human heart. Circulation 95, 568–571.PubMedGoogle Scholar
  157. 156.
    Hoppe U. C., Jansen E., Südkamp M., and Beuckelmann D. J. (1998) Hyperpolarization-activated inward current in ventricular myocytes from normal and failing human hearts. Circulation 97, 55–65.PubMedGoogle Scholar
  158. 157.
    Yu H., Chang F., and Cohen I. S. (1993) Pacemaker current exists in ventricular myocytes. Circ. Res. 72, 232–236.PubMedGoogle Scholar
  159. 158.
    Verkerk A. O., Wilders R., Coronel R., Ravesloot J. H., and Verheijck E. E. (2003) Ionic remodeling of sinoatrial node cells by heart failure. Circulation 108, 760–766.PubMedCrossRefGoogle Scholar
  160. 159.
    Cerbai E., Barbieri M., and Mugelli A. (1996) Occurrence and properties of the hyperpolarization-activated current If in ventricular myocytes from normotensive and hypertensive rats during aging. Circulation 94, 1674–1681.PubMedGoogle Scholar
  161. 160.
    Fernandez-Velasco M., Goren N., Benito G., Blanco-Rivero J., Bosca L., and Delgado C. (2003) Regional distribution of hyperpolarization-activated current (If) and hyperpolarization-activated cyclic nucleotide-gated channel mRNA expression in ventricular cells from control and hypertrophied rat hearts. J. Physiol. 553, 395–405.PubMedCrossRefGoogle Scholar
  162. 161.
    Hiramatsu M., Furukawa T., Sawanobori T., and Hiraoka M. (2002) Ion channel remodeling in cardiac hypertrophy is prevented by blood pressure reduction without affecting heart weight increase in rats with abdominal aortic banding. J. Cardiovasc. Pharm. 39, 866–874.CrossRefGoogle Scholar
  163. 162.
    Cerbai E., Crucitti A., Sartiani L., et al. (2000) Long-term treatment of spontaneously hypertensive rats with losartan and electrophysiological remodeling of cardiac myocytes. Cardiovasc. Res. 45, 388–396.PubMedCrossRefGoogle Scholar
  164. 163.
    Cerbai E., Pino R., Sartiani L., and Mugelli A. (1999) Influence of postnatal-development on If occurrence and properties in neonatal rat ventricular myocytes. Cardiovasc. Res. 42, 416–423.PubMedCrossRefGoogle Scholar
  165. 164.
    Toth Z., Yan X. X., Haftoglou S., Ribak C. E., and Baram T. Z. (1998) Seizure-induced neuronal injury: vulnerability to febrile seizures in an immature rat model. J. Neurosci. 18, 4285–4294.PubMedGoogle Scholar
  166. 165.
    Dube C., Chen K., Eghbal-Ahmadi M., Brunson K., Soltesz I., and Baram T. Z. (2000) Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term. Ann. Neurol. 47, 336–344.PubMedCrossRefGoogle Scholar
  167. 166.
    Walker M. C. and Kullmann D. M. (1999) Febrile convulsions: a “benign” condition? Nature Med. 5, 871, 872.PubMedCrossRefGoogle Scholar
  168. 167.
    Baram T. Z., Eghbal-Ahmadi M., and Bender R. A. (2002) Is neuronal death required for seizure-induced epileptogenesis in the immature brain? Prog. Brain Res. 135, 365–375.PubMedCrossRefGoogle Scholar
  169. 168.
    Chen K., Baram T. Z., and Soltesz I. (1999) Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits. Nat. Med. 5, 888–894.PubMedCrossRefGoogle Scholar
  170. 169.
    Chen K., Ratzliff A., Hilgenberg L., et al. (2003) Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron 39, 599–611.PubMedCrossRefGoogle Scholar
  171. 170.
    Chen K., Aradi I., Thon N., Eghbal-Ahmadi M., Baram T. Z., and Soltesz I. (2001) Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability. Nat. Med. 7, 331–337.PubMedCrossRefGoogle Scholar
  172. 171.
    Brewster A., Bender R. A., Chen Y., Dube C., Eghbal-Ahmadi M., and Baram T. Z. (2002) Developmental febrile seizures modulate hippocampal gene expression of hyperpolarization-activated channels in an isoform- and cell-specific manner. J. Neurosci. 22, 4591–4599.PubMedGoogle Scholar
  173. 172.
    Di Pasquale E., Keegan K. D., and Noebels J. L. (1997) Increased excitability and inward rectification in layer V cortical pyramidal neurons in the epileptic mutant mouse Stargazer. J. Neurophysiol. 77, 621–631.PubMedGoogle Scholar
  174. 173.
    Budde T., Caputi L., Kanyshkova T., Munsch T., Abrahamczik C., and Pape H. C. (2003) Electrophysiological and molecular characterization of hyperpolarization-activated cation channels in a rat model of absence epilepsy. Soc. Neurosci. Abstr. 212.17.Google Scholar
  175. 174.
    Bender R. A., Soleymani S. V., Brewster A. L., et al. (2003) Enhanced expression of a specific hyperpolarization-activated cyclic nucleotidegated cation channel (HCN) in surviving dentate gyrus granule cells of human and experimental epileptic hippocampus. J. Neurosci. 23, 6826–6836.PubMedGoogle Scholar
  176. 175.
    Isokawa M., Levesque M., Fried I., Jr. E. J. (1997) Glutamate currents in morphologically identified human dentate granule cells in temporal lobe epilepsy. J. Neurophysiol. 77, 3355–3369.PubMedGoogle Scholar
  177. 176.
    Poolos N. P., Migliore M., and Johnston D. (2002) Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nat. Neurosci. 5, 767–774.PubMedGoogle Scholar
  178. 177.
    Surges R., Freiman T. M., and Feuerstein T. J. (2003) Gabapentin increases the hyperpolarization-activated cation current Ih in rat CA1 pyramidal cells. Epilepsia 44, 150–156.PubMedCrossRefGoogle Scholar
  179. 178.
    Cosford N. D., Meinke P. T., Stauderman K. A., and Hess S. D. (2002) Recent advances in the modulation of voltage-gated ion channels for the treatment of epilepsy. Curr. Drug Target CNS Neurol Disord. 1, 81–104.CrossRefGoogle Scholar
  180. 179.
    Wickenden A. D. (2002) Potassium channels as anti-epileptic drug targets. Neuropharmacology 43, 1055–1060.PubMedCrossRefGoogle Scholar
  181. 180.
    Bräuer A. U., Savaskan N. E., Kole M. H. P., et al. (2001) Molecular and functional analysis of hyperpolarization-activated pacemaker channels in the hippocampus after entorhinal cortex lesion. FASEB J. 15, 2689–2701.PubMedCrossRefGoogle Scholar
  182. 181.
    Pachucki J., Burmeister L. A., and Larsen P. R. (1999) Thyroid hormone regulates hyperpolarization-activated cyclic nucleotide-gated channel (HCN2) mRNA in the rat heart. Circ. Res. 85, 498–503.PubMedGoogle Scholar
  183. 182.
    Brewster A. L., Simeone T. A., Bender R. A., and Baram T. Z. (2003) Mechanisms of activity-dependent regulation of hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) in developing hippocampus. Soc. Neurosci. Abstr. 369.6.Google Scholar
  184. 183.
    Rappaport Z. H. and Devor M. (1990) Experimental pathophysiological correlates of clinical symptomatology in peripheral neuropathic pain syndromes. Stereotact. Funct. Neurosurg. 55, 90–95.CrossRefGoogle Scholar
  185. 184.
    Shir Y. and Seltzer Z. (1990) A-fibers mediate mechanical hyperesthesia and allodynia and C-fibers mediate thermal hyperalgesia in a new model of causalgiform pain disorders in rats. Neurosci. Lett. 115, 62–67.PubMedCrossRefGoogle Scholar
  186. 185.
    Black J. A., Cummins T. R., Plumpton C., et al. (1999) Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. J. Neurophysiol. 82, 2776–2785.PubMedGoogle Scholar
  187. 186.
    Dib-Hajj S. D., Fjell J., Cummins T. R., et al. (1999) Plasticity of sodium channel expression in DRG neurons in the chronic constriction model of neuropathic pain. Pain 83, 591–600.PubMedCrossRefGoogle Scholar
  188. 187.
    Kim C. H., Oh Y., Chung J. M., and Chung K. (2001) The changes in expression of three subtypes of TTX sensitive sodium channels in sensory neurons after spinal nerve ligation. Mol. Brain Res. 95, 153–161.PubMedCrossRefGoogle Scholar
  189. 188.
    Waxman S. G. (2001) Transcriptional channelopathies: an emerging class of disorders. Nat. Rev. Neurosci. 2, 652–659.PubMedCrossRefGoogle Scholar
  190. 189.
    Chaplan S. R., Guo H.-Q., Lee D. H., et al. (2003) Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain. J. Neurosci. 23, 1169–1178.PubMedGoogle Scholar
  191. 190.
    Yao H., Donnelly D. F., Ma C., and LaMotte R. H. (2003) Upregulation of the hyperpolarization-activated cation current after chronic compression of the dorsal root ganglion. J. Neurosci. 23, 2069–2074.PubMedGoogle Scholar
  192. 191.
    Erdemli G. and Crunelli V. (1998) Response of thalamocortical neurons to hypoxia: a whole-cell patch-clamp study. J. Neurosci. 18, 5212–5224.PubMedGoogle Scholar
  193. 192.
    Linden D. R., Sharkey K. A., and Mawe G. M. (2003) Enhanced excitability of myenteric AH neurones in the inflamed guinea-pig distal colon. J. Physiol. 547, 589–601.PubMedCrossRefGoogle Scholar
  194. 193.
    Qu J., Cohen I. S., and Robinson R. B. (2000) Sympathetic innervation alters activation of pacemaker current (If) in rat ventricle. J. Physiol. 526, 561–569.PubMedCrossRefGoogle Scholar
  195. 194.
    Graf E. M., Heubach J. F., and Ravens U. (2001) The hyperpolarization-activated current If in ventricular myocytes of non-transgenic and β2-adrenoceptor overexpressing mice. Naunyn-Schmiedeberg’s Arch. Pharmacol. 364, 131–139.CrossRefGoogle Scholar
  196. 195.
    MacLean J. N., Zhang W., Johnson B. R., and Harris-Warrick R. M. (2003) Activity-independent homeostasis in rhythmically active neurons. Neuron 37, 109–120.PubMedCrossRefGoogle Scholar
  197. 196.
    Plotnikov A. N., Sosunov E. A., Qu J., et al. (2004) Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation 109, 506–512.PubMedCrossRefGoogle Scholar
  198. 197.
    Natomi T. and Shigemoto R. (2004) Immunohistochemical localization of Ih channel subunits, HCN1–4, in the rat brain. J. Comp. Neurol. 471, 241–276.CrossRefGoogle Scholar
  199. 198.
    van Welie, I., van Hoaft J. A., and Wadman W. J. (2004) Homeostatic scaling of neuronal excitability by synaptic modulation of somatic hyperpolarization-activated Ih channels. Proc. Natl. Acad. Sci. 101, 5123–5128.PubMedCrossRefGoogle Scholar
  200. 199.
    Shah M. M., Anderson A. E., Leung V., Lin X., and Johnston D. (2004) Seizure-induced plasticity of h channels in entorhinal cortical layer III pyramidal neurons. Neuron. 44, 495–508.PubMedCrossRefGoogle Scholar
  201. 200.
    Strauss U., Kole M. H., Brauer A. U., et al. (2004) An impaired neocortical Ih is associated with enhanced excitability and absence epilepsy. Eur. J. Neurosci. 19, 3048–3058.PubMedCrossRefGoogle Scholar
  202. 201.
    Berger T. and Luscher H. R. (2004) Associative somatodentritic interaction in layer V pyramidal neurons is not affected by the antiepileptic drug lamotrigine. Eur. J. Neurosci. 20, 1688–1693.PubMedCrossRefGoogle Scholar

Copyright information

© Human Press Inc 2004

Authors and Affiliations

  • Samuel G. A. Frère
    • 1
  • Mira Kuisle
    • 1
  • Anita Lüthi
    • 1
  1. 1.Section of Pharmacology and Neurobiology, BiozentrumUniversity of BaselBaselSwitzerland

Personalised recommendations