Regulation of HCN channel surface expression by a novel C-terminal protein-protein interaction
Open accessAbstract
Hyperpolarization-activated cation currents (I(h)) are carried by channels encoded by a family of four genes (HCN1-4) that are differentially expressed within the brain in specific cellular and subcellular compartments. HCN1 shows a high level of expression in apical dendrites of cortical pyramidal neurons and in presynaptic terminals of cerebellar basket cells, structures with a high density of I(h). Expression of I(h) is also regulated by neuronal activity. To isolate proteins that may control HCN channel expression or function, we performed yeast two-hybrid screens using the C-terminal cytoplasmic tails of the HCN proteins as bait. We identified a brain-specific protein, which has been previously termed TRIP8b (for TPR-containing Rab8b interacting protein) and PEX5Rp (for Pex5p-related protein), that specifically interacts with all four HCN channels through a conserved sequence in their C-terminal tails. In situ hybridization and immunohistochemistry show that TRIP8b and HCN1 are colocalized, particularly within dendritic arbors of hippocampal CA1 and neocortical layer V pyramidal neurons. The dendritic expression of TRIP8b in layer V pyramidal neurons is disrupted after deletion of HCN1 through homologous recombination, demonstrating a key in vivo interaction between HCN1 and TRIP8b. TRIP8b dramatically alters the trafficking of HCN channels heterologously expressed in Xenopus oocytes and human embryonic kidney 293 cells, causing a specific decrease in surface expression of HCN protein and I(h) density, with a pronounced intracellular accumulation of HCN protein that is colocalized in discrete cytoplasmic clusters with TRIP8b. Finally, TRIP8b expression in cultured pyramidal neurons markedly decreases native I(h) density. These data suggest a possible role for TRIP8b in regulating HCN channel density in the plasma membrane.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The difference in Ih sag between CA1 and CA2 neurons is consistent with higher levels of expression of the HCN1 subunit in CA1 neurons compared to CA2 or CA3 neurons.
“This difference is consistent with the higher levels of expression of the HCN1 subunit, which underlies Ih, in CA1 neurons compared to CA2 or CA3 neurons (Notomi and Shigemoto, 2004; Santoro et al., 2004).”
From Strong CA2 Pyramidal Neuron Synapses Define a Powerful Disynaptic Cortico-Hippocampal Loop (2010) · cites this paper as Santoro et al., 2004
HCN1 channels fail to accumulate in distal CA2 dendrites.
“In contrast, immunocytochemical light micrographs show that HCN1 channels fail to accumulate in the distal CA2 dendrites (Notomi and Shigemoto, 2004; Santoro et al., 2004).”
From Strong CA2 Pyramidal Neuron Synapses Define a Powerful Disynaptic Cortico-Hippocampal Loop (2010) · cites this paper as Santoro et al., 2004
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Rab proteins as membrane organizers
Zerial, M., & McBride, H. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35052055 · Cited by 3,381 · see citing works
Hyperpolarization-Activated Cation Currents: From Molecules to Physiological Function
Robinson, R. B., & Siegelbaum, S. A. (2003) · Annual Review of Physiology · doi:10.1146/annurev.physiol.65.092101.142734 · Cited by 1,177 · see citing works
Self-citationO’Dell, T. J., Hawkins, R. D., Kandel, E. R., & Arancio, O. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.24.11285 · Cited by 1,034 · see citing works
Magee, J. C. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-19-07613.1998 · Cited by 981 · see citing works
Identification of a Gene Encoding a Hyperpolarization-Activated Pacemaker Channel of Brain
Santoro, B., Liu, D. T., Yao, H., Bartsch, D., Kandel, E. R., Siegelbaum, S. A., & Tibbs, G. R. (1998) · Cell · doi:10.1016/s0092-8674(00)81434-8 · Cited by 705 · see citing works
Self-citationSantoro, B., Chen, S., Lüthi, A., Pavlidis, P., Shumyatsky, G. P., Tibbs, G. R., & Siegelbaum, S. A. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-14-05264.2000 · Cited by 600 · see citing works
Self-citationImmunohistochemical localization of Ih channel subunits, HCN1–4, in the rat brain
Notomi, T., & Shigemoto, R. (2004) · The Journal of Comparative Neurology · doi:10.1002/cne.11039 · Cited by 558 · see citing works
Auxiliary subunits: essential components of the voltage-gated calcium channel complex.
Arikkath, J., & Campbell, K. (2003) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(03)00066-7 · Cited by 536 · see citing works
Molecular mechanism of cAMP modulation of HCN pacemaker channels
Wainger, B. J., DeGennaro, M., Santoro, B., Siegelbaum, S. A., & Tibbs, G. R. (2001) · Nature · doi:10.1038/35081088 · Cited by 520 · see citing works
Self-citationA Behavioral Role for Dendritic Integration
Nolan, M. F., Malleret, G., Dudman, J. T., Buhl, D. L., Santoro, B., Gibbs, E., Vronskaya, S., Buzsáki, G., Siegelbaum, S. A., Kandel, E. R., et al. (2004) · Cell · doi:10.1016/j.cell.2004.11.020 · Cited by 472 · see citing works
Self-citationPolarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites
Lőrincz, A., Notomi, T., Tamás, G., Shigemoto, R., & Nusser, Z. (2002) · Nature Neuroscience · doi:10.1038/nn962 · Cited by 442 · see citing works
Chen, K., Aradi, I., Thon, N., Eghbal-Ahmadi, M., Baram, T. Z., & Soltész, I. (2001) · Nature Medicine · doi:10.1038/85480 · Cited by 427 · see citing works
Moosmang, S., Stieber, J., Zong, X., Biel, M., Hofmann, F. B., & Ludwig, A. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.02036.x · Cited by 415 · see citing works
Peroxisomal targeting signal-1 recognition by the TPR domains of human PEX5.
Berg, J. M., Gatto, G. J. J., Geisbrecht, B. V., & Gould, S. J. (2000) · Nature Structural Biology · doi:10.1038/81930 · Cited by 363 · see citing works
Xu, S., & Beech, D. J. (2001) · Circulation Research · doi:10.1161/01.res.88.1.84 · Cited by 361 · see citing works
Molecular organization of the postsynaptic specialization
Sheng, M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111146298 · Cited by 336 · see citing works
Neuronal Hyperpolarization-Activated Pacemaker Channels Drive Neuropathic Pain
Chaplan, S. R., Guo, H.-Q., Lee, D. H., Luo, L., Liu, C., Kuei, C., Velumian, A. A., Butler, M. P., Brown, S. M., & Dubin, A. E. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-04-01169.2003 · Cited by 335 · see citing works
Nolan, M. F., Malleret, G., Lee, K. H., Gibbs, E., Dudman, J. T., Santoro, B., Yin, D., Thompson, R. F., Siegelbaum, S. A., Kandel, E. R., et al. (2003) · Cell · doi:10.1016/s0092-8674(03)00884-5 · Cited by 320 · see citing works
Self-citationBerger, T. K., Larkum, M. E., & Lüscher, H. (2001) · Journal of Neurophysiology · doi:10.1152/jn.2001.85.2.855 · Cited by 286 · see citing works
Santoro, B., Grant, S. G. N., Bartsch, D., & Kandel, E. R. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.26.14815 · Cited by 275 · see citing works
Self-citationActivity-Independent Homeostasis in Rhythmically Active Neurons
MacLean, J. N., Zhang, Y., Johnson, B. R., & Harris‐Warrick, R. M. (2003) · Neuron · doi:10.1016/s0896-6273(02)01104-2 · Cited by 272 · see citing works
Brewster, A. L., Bender, R. A., Chen, Y., Dubé, C. M., Eghbal-Ahmadi, M., & Baram, T. Z. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-11-04591.2002 · Cited by 270 · see citing works
Yu, H., Wu, J., Potapova, I. A., Wymore, R. T., Holmes, B., Zuckerman, J. J., Pan, Z., Wang, H. Q., Shi, W., Robinson, R., et al. (2001) · Circulation Research · doi:10.1161/hh1201.093511 · Cited by 254 · see citing works
Peränen, J., Auvinen, P., Virta, H., Wepf, R. A., & Simons, K. (1996) · The Journal of Cell Biology · doi:10.1083/jcb.135.1.153 · Cited by 247 · see citing works
Drake, C. T., Milner, T. A., & Patterson, S. L. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-18-08009.1999 · Cited by 221 · see citing works
van Welie, I., van Hooft, J. A., & Wadman, W. J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307711101 · Cited by 182 · see citing works
In Situ Hybridization Protocols for the Brain
Wisden, W., & MORRIS, B. J. (2002) · International review of neurobiology · doi:10.1016/s0074-7742(00)x0008-6 · Cited by 136 · see citing works
Bidirectional Changes in Spatial Dendritic Integration Accompanying Long-Term Synaptic Modifications
Wang, Z., Xu, N.-L., Wu, C.-P., Duan, S., & Poo, M. (2003) · Neuron · doi:10.1016/s0896-6273(02)01189-3 · Cited by 131 · see citing works
MiRP1 Modulates HCN2 Channel Expression and Gating in Cardiac Myocytes
Qu, J., Kryukova, Y. N., Potapova, I. A., Doronin, S. V., Larsen, M., Krishnamurthy, G., Cohen, I. S., & Robinson, R. B. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405018200 · Cited by 129 · see citing works
Vasilyev, D. V., & Barish, M. E. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-20-08992.2002 · Cited by 126 · see citing works
The multiple personalities of h-channels
Santoro, B., & Baram, T. Z. (2003) · Trends in Neurosciences · doi:10.1016/j.tins.2003.08.003 · Cited by 123 · see citing works
Self-citationProtein transport to the dendritic plasma membrane of cultured neurons is regulated by rab8p.
Huber, L. A., de Hoop, M. J., Dupree, P., Zerial, M., Simons, K., & Dotti, C. G. (1993) · The Journal of Cell Biology · doi:10.1083/jcb.123.1.47 · Cited by 123 · see citing works
Bender, R. A., Brewster, A. L., Santoro, B., Ludwig, A., Hofmann, F. B., Biel, M., & Baram, T. Z. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00314-1 · Cited by 117 · see citing works
Self-citationSpatial and temporal expression of cone opsins during monkey retinal development
O’Brien, K. M. B., Jasoni, C. L., Sz�l, A., & Hendrickson, A. E. (1997) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19970203)378:1 · Cited by 100 · see citing works
Electrophysiology of embryonic, adult and aged rat hippocampal neurons in serum-free culture
Evans, M. S., Collings, M. A., & Brewer, G. J. (1998) · Journal of Neuroscience Methods · doi:10.1016/s0165-0270(97)00159-3 · Cited by 98 · see citing works
Hyperpolarization-activated chloride currents in Xenopus oocytes.
Kowdley, G. C., Ackerman, S. J., John, J. E., et al. (1994) · The Journal of General Physiology · doi:10.1085/jgp.103.2.217 · Cited by 92 · see citing works
Xue, T., Marbán, E., & Li, R. A. (2002) · Circulation Research · doi:10.1161/01.res.0000024390.97889.c6 · Cited by 85 · see citing works
Functional Roles of Charged Residues in the Putative Voltage Sensor of the HCN2 Pacemaker Channel
Chen, J., Mitcheson, J. S., Lin, M. J.-Y., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m007034200 · Cited by 80 · see citing works
Bräuer, A. U., Savaskan, N. E., Kole, M. H. P., Plaschke, M., Monteggia, L. M., Nestler, E. J., Simbürger, E., Deisz, R. A., Ninnemann, O., & Nitsch, R. (2001) · The FASEB Journal · doi:10.1096/fj.01-0235com · Cited by 59 · see citing works
Rab8b and Its Interacting Partner TRIP8b Are Involved in Regulated Secretion in AtT20 Cells
Chen, S., Liang, M. C., Chia, J. N., Ngsee, J. K., & Ting, A. E. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010798200 · Cited by 58 · see citing works
Kass, R. S. (2003) · Trends in Cardiovascular Medicine · doi:10.1016/s1050-1738(02)00211-6 · Cited by 39 · see citing works
Amery, L., Sano, H., Mannaerts, G. P., Snider, J. D., Jeroen van, L. O. O. Y., Fransen, M., & Veldhoven, P. P. V. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3570635 · Cited by 37 · see citing works
Receptor and Ion channel Trafficking
Henley, J. M., & Moss, S. J. (2002) · Bristol Research (University of Bristol) · Cited by 9 · see citing works
The hybridoma revolution: an offshoot of basic research
Milstein, C. (1999) · BioEssays · doi:10.1002/(sici)1521-1878(199911)21:11 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Strong CA2 Pyramidal Neuron Synapses Define a Powerful Disynaptic Cortico-Hippocampal Loop
Chevaleyre, V., & Siegelbaum, S. A. (2010) · Neuron · doi:10.1016/j.neuron.2010.04.013 · Cited by 324 · see citing works
Self-citationKalmbach, B. E., Buchin, A., Long, B., Close, J., Nandi, A., Miller, J. A., Bakken, T. E., Hodge, R. D., Chong, P., de Frates, R., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.012 · Cited by 203 · see citing works
Cortical HCN channels: Function, trafficking and plasticity
Shah, M. M. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2013.270058 · Cited by 160 · see citing works
Sartiani, L., Mannaioni, G., Masi, A., Novella Romanelli, M., & Cerbai, E. (2017) · Pharmacological Reviews · doi:10.1124/pr.117.014035 · Cited by 143 · see citing works
Santoro, B., & Shah, M. M. (2020) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010919-023356 · Cited by 108 · see citing works
Self-citationIh from synapses to networks: HCN channel functions and modulation in neurons
Combe, C. L., & Gasparini, S. (2021) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2021.06.002 · Cited by 101 · see citing works
Kim, J., Lei, Y., Lu, X.-Y., & Kim, C. S. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01682-9 · Cited by 33 · see citing works
CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny
Assendorp, N., Fossati, M., Libé-Philippot, B., Christopoulou, E., Depp, M., Rapone, R., Dingli, F., Loew, D., Vanderhaeghen, P., & Charrier, C. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114797 · Cited by 32 · see citing works
Lyman, K. A., Han, Y., Zhou, C., Renteria, I., Besing, G.-L., Kurz, J. E., & Chetkovich, D. M. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abl4580 · Cited by 17 · see citing works
- Authors
- Santoro, B., Wainger, B. J., & Siegelbaum, S. A.
- Affiliations
- Columbia University (US)
- Howard Hughes Medical Institute (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-11-24
- Volume
- 24
- Issue
- 47
- Pages
- 10750-10762
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6730122
- OpenAlex
- W2013575118
- Cited by
- 210
- References
- 44
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 7 · 2023: 7 · 2022: 12 · 2021: 9 · 2020: 10 · 2019: 9 · 2018: 13 · 2017: 11 · 2016: 5 · 2015: 9 · 2014: 13 · 2013: 12 · 2012: 14
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS036658, NS36658, R56NS036658)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- HCN channels, hyperpolarization-activated current, TRIP8b, channel surface expression, channel trafficking, HCN1, pyramidal neurons, dendritic localization, hippocampal CA1, neuronal activity regulation
- MeSH terms
- Peroxins, Action Potentials, Amino Acid Sequence, Animals, Brain, Cells, Cultured, Gene Expression Regulation, Cricetinae, Humans, Ion Channels, Membrane Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Protein Binding, Recombinant Fusion Proteins, Sindbis Virus, Xenopus laevis, Conserved Sequence, Rats, Sprague-Dawley, Pyramidal Cells, Mice, Knockout, Protein Isoforms, Amino Acid Motifs, Protein Transport, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
