Ca V 3.1 is a tremor rhythm pacemaker in the inferior olive
Open accessAbstract
The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of Ca V 3.1 T-type Ca 2+ channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4- to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking Ca V 3.1 gene. Intracellular recordings in brain-stem slices revealed that the Ca V 3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of Ca V 3.1 gene in the inferior olive by sh RNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate Ca V 3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, Ca V 3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor.
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T-type calcium channels are a powerful mechanism by which the IO regulates cerebellar output.
“Moreover, T-type calcium channels are a powerful mechanism by which the IO regulates cerebellar output [269].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [269]
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Essential Tremor - a cerebellar driven disorder?
Ibrahim, M. F., Beevis, J. C., & Empson, R. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.11.002 · Cited by 27 · see citing works
A Phase 2 Proof‐of‐Concept, Randomized, Placebo‐Controlled Trial of CX ‐8998 in Essential Tremor
Papapetropoulos, S., Lee, M. S., Versavel, S., Newbold, E. J., Jinnah, H. A., Pahwa, R., Lyons, K. E., Elble, R. J., Ondo, W. G., Zesiewicz, T., et al. (2021) · Movement Disorders · doi:10.1002/mds.28584 · Cited by 31 · see citing works
Kosmowska, B., & Wardas, J. (2021) · Biomolecules · doi:10.3390/biom11121813 · Cited by 31 · see citing works
T‐type calcium channels as therapeutic targets in essential tremor and Parkinson's disease
Matthews, L. G., Puryear, C. B., Correia, S. S., Srinivasan, S. R., Belfort, G. M., Pan, M., & Kuo, S. (2023) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51735 · Cited by 30 · see citing works
“, neuronal oscillations that occur as a result of intrinsic membrane potential fluctuations but which are below the voltage threshold required to cause a neuron to fire) are dependent on TTCC conductance(148) and closely associated with generation of tremor rhythm, and have been shown to be amplified in IO neurons fol…”
BackgroundAtaxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42
Hashiguchi, S., Doi, H., Kunii, M., Nakamura, Y., Shimuta, M., Suzuki, E., Koyano, S., Okubo, M., Kishida, H., Shiina, M., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104516 · Cited by 27 · see citing works
Genetics of essential tremor: From phenotype to genes, insights from both human and mouse studies
Schmouth, J.-F., Dion, P. A., & Rouleau, G. A. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2014.05.001 · Cited by 26 · see citing works
“1 T-type Ca 2+) (Park et al., 2010).”
Caro-Martín, C. R., Leal‐Campanario, R., Sánchez‐Campusano, R., Delgado-Garcia, J. M., & Gruart, A. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.2285-15.2015 · Cited by 24 · see citing works
Senatore, A., Zhorov, B. S., & Spafford, J. (2012) · Wiley Interdisciplinary Reviews Membrane Transport and Signalling · doi:10.1002/wmts.41 · Cited by 31 · see citing works
Choi, K.-H. (2013) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2013.796926 · Cited by 22 · see citing works
“1 T-type channels in inferior olivary neurons resulted in suppression of harmalineinduced tremor in mice [66].”
BackgroundPapapetropoulos, S., Lee, M. S., Boyer, S., & Newbold, E. J. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00597 · Cited by 22 · see citing works
“Tremor-related oscillations in the olivocerebellar pathway are key abnormalities underlying ET and trigger onset of tremor-related rhythms (38).”
BackgroundSwitchable slow cellular conductances determine robustness and tunability of network states
Drion, G., Dethier, J., Franci, A., & Sepulchre, R. J. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006125 · Cited by 21 · see citing works
Inferior Olive: All Ins and Outs
Gruijl, J. R. D., Bosman, L. W. J., Zeeuw, C. I. D., & de Jeu, M. T. G. (2012) · Springer eBooks · doi:10.1007/978-94-007-1333-8_43 · Cited by 19 · see citing works
Two-phase model of the basal ganglia: implications for discontinuous control of the motor system
Lisman, J. E. (2014) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2013.0489 · Cited by 18 · see citing works
Chang, K.-Y., Park, Y.-G., Park, H., Homanics, G. E., Kim, J.-J., & Kim, D. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.05.082 · Cited by 18 · see citing works
Self-citationZutt, R., Elting, J., & Tijssen, M. (2019) · Handbook of Clinical Neurology · doi:10.1016/b978-0-444-64142-7.00046-1 · Cited by 8 · see citing works
Scott, L., Puryear, C. B., Belfort, G. M., Raines, S. R., Hughes, Z. A., Matthews, L. G., Ravina, B. M., & Wittmann, M. (2022) · Movement Disorders · doi:10.1002/mds.28969 · Cited by 17 · see citing works
Effects of Alprazolam on Cortical Activity and Tremors in Patients with Essential Tremor
Ibáñez, J., de la Aleja, J. G., Gallego, J. Á., Romero, J. P., Díaz, R. A. S., Benito‐León, J., & Rocón, E. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093159 · Cited by 17 · see citing works
“Regardless of whether ET is a neurodegenerative disease affecting PC [51], or the result of pacemaking neurons in the inferior olive [48–50], these structures are controlled by GABAergic connections [52].”
BackgroundDual role of T-type calcium channels in anxiety-related behavior
Kaur, S., Маслов, Л. Н., Singh, N., & Jaggi, A. S. (2019) · Journal of Basic and Clinical Physiology and Pharmacology · doi:10.1515/jbcpp-2019-0067 · Cited by 17 · see citing works
The potential roles of T-type Ca2+ channels in motor coordination
Park, Y.-G., Kim, J. J., & Kim, D. (2013) · Frontiers in Neural Circuits · doi:10.3389/fncir.2013.00172 · Cited by 16 · see citing works
“Once the neural circuits are defined, then isoformspecific knockdowns of T-type Ca2+ channels (Park et al., 2010) can be applied to identified circuits.”
BackgroundInfluentialSelf-citationHypertrophic Olivary Degeneration Does Not Reduce Essential Tremor
Elkouzi, A., Kattah, J. C., & Elble, R. J. (2015) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.12275 · Cited by 16 · see citing works
“The inferior olive is postulated to play a critical role in the generation of essential tremor (ET) and palatal tremor.(1) The olivary hypothesis of ET stems mainly from the harmaline animal model, in which action tremor resembling ET is caused by harmaline-induced olivary oscillation.”
BackgroundNew Perspectives for Computer-Aided Discrimination of Parkinson’s Disease and Essential Tremor
Povalej, P., Gallego, J. Á., Romero, J. P., Glaser, V., Rocón, E., Benito‐León, J., Bermejo‐Pareja, F., Posada, I. J., & Holobar, A. (2017) · Complexity · doi:10.1155/2017/4327175 · Cited by 16 · see citing works
Schaefer, S. M., Vives‐Rodriguez, A., & Louis, E. D. (2017) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2018.1413353 · Cited by 16 · see citing works
An Update on the Neurochemistry of Essential Tremor
Jiménez‐Jiménez, F. J., Alonso‐Navarro, H., García‐Martín, E., & Agúndez, J. A. G. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666181112094330 · Cited by 16 · see citing works
Wang, Y., Liu, C.-W., Chen, S., Lu, L., Liu, W.-C., Wang, J., Ni, C., Wong, S., Kumar, A., Lee, J., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adl1408 · Cited by 15 · see citing works
Heterogeneity of tremor mechanisms assessed by tremor-related cortical potential in mice
Park, Y.-G., Choi, J. H., Lee, C., Kim, S., Kim, Y. S., Chang, K.-Y., Paek, S. H., & Kim, D. (2015) · Molecular Brain · doi:10.1186/s13041-015-0093-2 · Cited by 15 · see citing works
Self-citationSeol, M., & Kuner, T. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.13084 · Cited by 15 · see citing works
“8A) (Park et al., 2010).”
BackgroundMethodInfluentialHarmaline Attenuates Voltage - Sensitive Ca2+ Currents in Neurons of the Inferior Olive
Zhan, X., & Graf, W. M. (2012) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/j3w595 · Cited by 15 · see citing works
“The concentrations we investigated for both voltage and current clamp recording are larger than that Park et al used (0.001~ 0.1 mM) for voltage clamp, but slightly smaller than that used for current clamp recording (0.1 mg/ml or 0.35 mM) (17).”
BackgroundMethodResultInfluentialOculopalatal Tremor: Variations on a Theme by Guillain and Mollaret
Jang, L., & Borruat, F. (2014) · European Neurology · doi:10.1159/000360531 · Cited by 14 · see citing works
Non-invasive Central and Peripheral Stimulation: New Hope for Essential Tremor?
Chalah, M. A., Lefaucheur, J., & Ayache, S. S. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00440 · Cited by 14 · see citing works
D’Apolito, M., Ceccarini, C., Savino, R., Adipietro, I., di Bari, I., Santacroce, R., Curcetti, M., D’Andrea, G., Croce, A.-I., Cesarano, C., et al. (2023) · Genes · doi:10.3390/genes14071380 · Cited by 13 · see citing works
“1 gene expression in the inferior olive neurons efficiently suppressed harmaline-induced tremor in wild-type mice [9].”
BackgroundKunisawa, N., Shimizu, S., Kato, M., Iha, H. A., Iwai, C., Hashimura, M., Ogawa, M., Kawaji, S., Kawakita, K., Abé, K., et al. (2018) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2018.05.007 · Cited by 13 · see citing works
Is the inferior olive central to essential tremor? Yes
Lang, E. J., & Handforth, A. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.02.009 · Cited by 13 · see citing works
Bazzigaluppi, P., & de Jeu, M. T. G. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00192 · Cited by 12 · see citing works
“1 -/- mutant mice (Choi et al., 2010; Park et al., 2010).”
BackgroundCharacteristics of Tremor Induced by Lesions of the Cerebellum
Kovács, A., Kiss, M., Pinter, N. K., Szirmai, I. G., & Kamondi, A. (2019) · The Cerebellum · doi:10.1007/s12311-019-01027-3 · Cited by 12 · see citing works
“1 channels’ responsiveness, or the inferior olive might also be needed for sustained tremor [8].”
BackgroundEssential Tremor—Do We Have Better Therapeutics? A Review of Recent Advances and Future Directions
Shetty, N. (2022) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-022-01185-8 · Cited by 10 · see citing works
Post-Inhibitory Rebound Firing of Dorsal Root Ganglia Neurons
Zhu, T., Wei, S., & Wang, Y. (2022) · Journal of Pain Research · doi:10.2147/jpr.s370335 · Cited by 11 · see citing works
Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity
Feng, B. C., Harms, J., Patel, N., Ye, H., Luo, P., Irizarry, V. C. T., Vidrine, J., Coulter, A. A., Rebello, C. J., Yu, S., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101391 · Cited by 11 · see citing works
Shukla, A. W. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.02.008 · Cited by 12 · see citing works
Mechanisms and Pharmacotherapy for Ethanol-Responsive Movement Disorders
Wu, J., Tang, H., Chen, S., & Cao, L. H. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00892 · Cited by 11 · see citing works
Gong, Y., Liu, R., Zha, H.-J., Dong, D., Lu, N., Yan, H., Wan, L.-S., & Nian, Y. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202313461 · Cited by 10 · see citing works
Enhancing GABA inhibition is the next generation of medications for essential tremor
Ondo, W. G. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.02.007 · Cited by 9 · see citing works
Mukherjee, A., & Pandey, S. (2025) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.70147 · Cited by 8 · see citing works
Agmatine has beneficial effect on harmaline-induced essential tremor in rat
Akman, Ö., Utkan, T., Arıcıoğlu, F., Güllü, M. K., Ateş, N., & Karson, A. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.135881 · Cited by 8 · see citing works
Mapping BOLD Activation by Pharmacologically Evoked Tremor in Swine
Lee, J., Jo, H. J., Kim, I., Lee, J., Min, H.-K. P., In, M., Knight, E. J., & Chang, S.-Y. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00985 · Cited by 8 · see citing works
Implications of Electrical Synapse Plasticity in the Inferior Olive
Welsh, J. P., & Turecek, J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-803471-2.00012-6 · Cited by 7 · see citing works
Thalamo-cortical network is associated with harmaline-induced tremor in rodent model
Lee, J., Kim, J., Cortez, J., & Chang, S.-Y. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114210 · Cited by 7 · see citing works
Targeting the fundamentals for tremors: the frequency and amplitude coding in essential tremor
Pan, M. (2025) · Journal of Biomedical Science · doi:10.1186/s12929-024-01112-8 · Cited by 9 · see citing works
Is essential tremor a disorder of GABA dysfunction? No
Bellows, S. T., & Shahed, J. J. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.02.006 · Cited by 7 · see citing works
Overcoming Depression by Inhibition of Neural Burst Firing
Kim, D., Cheong, E., & Shin, H. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.032 · Cited by 7 · see citing works
Self-citationDeep Brain Stimulation for Essential Tremor
Morigaki, R., & Goto, S. (2015) · Springer eBooks · doi:10.1007/978-3-319-08476-3_11 · Cited by 92 · see citing works
Sharifi, S., Luft, F., de Boer, L., Buijink, A. W. G., Mugge, W., Schouten, A. C., Heida, T., Bour, L. J., & van Rootselaar, A. (2022) · NeuroImage · doi:10.1016/j.neuroimage.2022.119554 · Cited by 6 · see citing works
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“1 is highly expressed in the inferior olive and cerebellum and is involved in the generation of tremorrelated rhythms [11].”
BackgroundCerebellar nuclei neurons display aberrant oscillations during harmaline-induced tremor
Baumel, Y., Yamin, H. G., & Cohen, D. (2021) · Heliyon · doi:10.1016/j.heliyon.2021.e08119 · Cited by 6 · see citing works
“Harmaline induces network oscillations at about 10 Hz, originating in the IO and spreading into the cerebellar cortex and the CN (Milner et al., 1995; Llinas and Volkind, 1973; Park et al., 2010).”
BackgroundTreatment of intractable resting tremor of spinocerebellar ataxia 42 with zonisamide
Hara, N., Nezu, T., Kobatake, K., Morino, H., Kawakami, H., & Maruyama, H. (2018) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2018.11.013 · Cited by 6 · see citing works
Imaging Subthreshold Voltage Oscillation With Cellular Resolution in the Inferior Olive in vitro
Dorgans, K., Kühn, B., & Uusisaari, M. Y. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.607843 · Cited by 6 · see citing works
Is inferior olive central to the pathophysiology of essential tremor? No
Manto, M. U. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.02.010 · Cited by 6 · see citing works
Harmaline toxicity on dorsal striatal neurons and its role in tremor
Zhan, X., Do, L. V., Zou, L. B., Zhan, R. S., Jones, M., Nawaz, S., & Manaye, K. F. (2023) · NeuroToxicology · doi:10.1016/j.neuro.2023.10.005 · Cited by 5 · see citing works
von der Gablentz, J., Sprenger, A., Heldmann, M., Münte, T. F., & Helmchen, C. (2013) · Journal of Neurology · doi:10.1007/s00415-013-7059-z · Cited by 5 · see citing works
- Authors
- Park, Y.-G., Park, H.-Y., Lee, C. J., Choi, S., Jo, S., Choi, H., Kim, Y.-H., Shin, H.-S., Llinas, R. R., & Kim, D.
- Affiliations
- Korea Advanced Institute of Science and Technology (KR)
- Korea Institute of Science and Technology (KR)
- New York University (US)
- Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016; and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-05-24
- Volume
- 107
- Issue
- 23
- Pages
- 10731-10736
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2890811
- OpenAlex
- W2075318347
- Cited by
- 142
- References
- 45
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 14 · 2021: 9 · 2020: 8 · 2019: 15 · 2018: 7 · 2017: 8 · 2016: 2 · 2015: 12 · 2014: 12 · 2013: 9 · 2012: 16
- FWCI
- 6.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Science and Technology
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS 13742, P01NS013742)
- Topics
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- 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
- Keywords
- Cav3.1, T-type calcium channels, inferior olive, essential tremor, pathological tremor, pacemaker neurons, harmaline, neural oscillations, shRNA knockdown
- MeSH terms
- Animals, Cell Line, Disease Models, Animal, Harmaline, Humans, Male, Mice, Inbred C57BL, Olivary Nucleus, Tremor, Mice, Knockout, Calcium Channels, T-Type, RNA Interference, Mice
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