SpringerLink
Log in

From Calcium Channels to New Therapeutics

  • Chapter
  • First Online:
Voltage-Gated Calcium Channels

Abstract

An ultimate goal of biomedical research into calcium channels is to enable better treatment of disease, most prominently through the development of experimental therapeutics for unaddressed medical needs. As described throughout this book, voltage-gated calcium channels unquestionably are key control points for a diversity of physiological and pathophysiological mechanisms, particularly in excitable cells. Leveraging such biological information into successful therapeutics requires many scientific, clinical, and strategic steps, starting from robust validation for the role of an individual target in disease. Calcium channels are the targets for several drugs with a trajectory that now can be seen from conception to maturity, showing some key determinants of success. This chapter reviews the development of nifedipine and dihydropyridines, pregabalin and gabapentin, and ziconotide, which are clinically effective via inhibition of Cav1 L-type channels, Cavα2δ1/2, and Cav2.2 N-type channels, respectively. Emerging tools and resources for drug discovery are highlighted, particularly the genetic and genomic resources increasingly used to find molecular intervention points from an untargeted perspective. Finally, this chapter surveys the ongoing development of experimental therapeutics targeting Cav3 T-type, Cav1, and other calcium channels, including experimental treatments for Parkinson’s, essential tremor, psychiatric diseases, and epilepsy, in light of the drug discovery flow path.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
EUR 29.95
Price includes VAT (France)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
EUR 160.49
Price includes VAT (France)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
EUR 210.99
Price includes VAT (France)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info
Hardcover Book
EUR 210.99
Price includes VAT (France)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Andrade, A., Brennecke, A., Mallat, S., Brown, J., Gomez-Rivadeneira, J., Czepiel, N., & Londrigan, L. (2019). Genetic associations between voltage-gated calcium channels and psychiatric disorders. International Journal of Molecular Sciences, 20(14), 3537. https://doi.org/10.3390/ijms20143537

    Article  CAS  PubMed Central  Google Scholar 

  • Andrade, A., Hope, J., Allen, A., Yorgan, V., Lipscombe, D., & Pan, J. Q. (2016). A rare schizophrenia risk variant of CACNA1I disrupts Cav3.3 channel activity. Scientific Reports, 6, 34233. https://doi.org/10.1038/srep34233

  • Azari, S., Rezapour, A., Omidi, N., Alipour, V., Behzadifar, M., Safari, H., Tajdini, M., & Bragazzi, N. L. (2020). Cost-effectiveness analysis of PCSK9 inhibitors in cardiovascular diseases: A systematic review. Heart Failure Reviews, 25, 1077–1088.

    Article  PubMed  Google Scholar 

  • Azzouz, M., Ralph, G. S., Storkebaum, E., Walmsley, L. E., Mitrophanous, K. A., Kingsman, S. M., Carmeliet, P., & Mazarakis, N. D. (2004). VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature, 429, 413–417.

    Article  CAS  PubMed  Google Scholar 

  • Backonja, M., & Glanzman, R. L. (2003). Gabapentin dosing for neuropathic pain: Evidence from randomized, placebo-controlled clinical trials. Clinical Therapeutics, 25, 81–104.

    Article  CAS  PubMed  Google Scholar 

  • Balemans, W., Ebeling, M., Patel, N., Van Hul, E., Olson, P., Dioszegi, M., Lacza, C., Wuyts, W., Van Den Ende, J., Willems, P., Paes-Alves, A. F., Hill, S., Bueno, M., Ramos, F. J., Tacconi, P., Dikkers, F. G., Stratakis, C., Lindpaintner, K., Vickery, B., … Van Hul, W. (2001). Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Human Molecular Genetics, 10, 537–543.

    Article  CAS  PubMed  Google Scholar 

  • Barclay, J., Balaguero, N., Mione, M., Ackerman, S. L., Letts, V. A., Brodbeck, J., Canti, C., Meir, A., Page, K. M., Kusumi, K., Perez-Reyes, E., Lander, E. S., Frankel, W. N., Gardiner, R. M., Dolphin, A. C., & Rees, M. (2001). Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells. The Journal of Neuroscience, 21, 6095–6104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bean, B. P. (1984). Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state. Proceedings. National Academy of Sciences. United States of America, 81(20), 6388–6392. https://doi.org/10.1073/pnas.81.20.6388

  • Bertrand, S., Ng, G. Y., Purisai, M. G., Wolfe, S. E., Severidt, M. W., Nouel, D., Robitaille, R., Low, M. J., O’Neill, G. P., Metters, K., Lacaille, J. C., Chronwall, B. M., & Morris, S. J. (2001). The anticonvulsant, antihyperalgesic agent gabapentin is an agonist at brain gamma-aminobutyric acid type B receptors negatively coupled to voltage-dependent calcium channels. The Journal of Pharmacology and Experimental Therapeutics, 298, 15–24.

    CAS  PubMed  Google Scholar 

  • Bendels, S., Bissantz, C., Fasching, B. et al. (2019). Safety screening in early drug discovery: An optimized assay panel. Journal of Pharmacological and Toxicological Methods, 99. https://doi.org/10.1016/j.vascn.2019.106609

  • Biglan, K. M., Oakes, D., Lang, A. E., Hauser, R. A., Hodgeman, K., Greco, B., Lowell, J., Rockhill, R., Shoulson, I., Venuto, C., Young, D., Simuni, T., & Parkinson Study Group S-PDIIII. (2017). A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY-PD III). Annals of Clinical Translational Neurology, 4, 360–368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blauw, L. L., Li-Gao, R., Noordam, R., de Mutsert, R., Trompet, S., Berbee, J. F. P., Wang, Y., van Klinken, J. B., Christen, T., van Heemst, D., Mook-Kanamori, D. O., Rosendaal, F. R., Jukema, J. W., Rensen, P. C. N., & Willems van Dijk, K. (2018). CETP (Cholesteryl Ester Transfer Protein) concentration: A genome-wide association study followed by Mendelian randomization on coronary artery disease. Circulation: Genomic and Precision Medicine, 11, e002034.

    CAS  Google Scholar 

  • Blauw, L. L., Noordam, R., Soidinsalo, S., Blauw, C. A., Li-Gao, R., de Mutsert, R., Berbee, J. F. P., Wang, Y., van Heemst, D., Rosendaal, F. R., Jukema, J. W., Mook-Kanamori, D. O., Wurtz, P., Willems van Dijk, K., & Rensen, P. C. N. (2019). Mendelian randomization reveals unexpected effects of CETP on the lipoprotein profile. European Journal of Human Genetics, 27, 422–431.

    Article  CAS  PubMed  Google Scholar 

  • Bockbrader, H. N., Wesche, D., Miller, R., et al. (2010). A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clinical Pharmacokinetics, 49, 661–669.

    Article  CAS  PubMed  Google Scholar 

  • Bossert, F., & Vater, W. (1989). 1,4-Dihydropyridines—A basis for develo** new drugs. Medicinal Research Reviews, 9, 291–324.

    Article  CAS  PubMed  Google Scholar 

  • Bourinet, E., Francois, A., & Laffray, S. (2016). T-type calcium channels in neuropathic pain. Pain, 157(Suppl 1), S15–S22.

    Article  PubMed  Google Scholar 

  • Brodbeck, J., Davies, A., Courtney, J. M., Meir, A., Balaguero, N., Canti, C., Moss, F. J., Page, K. M., Pratt, W. S., Hunt, S. P., Barclay, J., Rees, M., & Dolphin, A. C. (2002). The ducky mutation in Cacna2d2 results in altered Purkinje cell morphology and is associated with the expression of a truncated alpha 2 delta-2 protein with abnormal function. The Journal of Biological Chemistry, 277, 7684–7693.

    Article  CAS  PubMed  Google Scholar 

  • Brookes, M. E., Eldabe, S., & Batterham, A. (2017). Ziconotide monotherapy: A systematic review of randomised controlled trials. Current Neuropharmacology, 15, 217–231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bryans, J. S., & Wustrow, D. J. (1999). 3-substituted GABA analogs with central nervous system activity: A review. Medicinal Research Reviews, 19, 149–177.

    Article  CAS  PubMed  Google Scholar 

  • Burges, R., & Moisey, D. (1994). Unique pharmacologic properties of amlodipine. The American Journal of Cardiology, 73(3), A2–A9. https://doi.org/10.1016/0002-9149(94)90268-2

  • Burdge, G., Leach, H., & Walsh, K. (2018). Ziconotide-induced psychosis: A case report and literature review. The Mental Health Clinician, 8, 242–246.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cain, S. M., Tyson, J. R., Jones, K. L., & Snutch, T. P. (2015). Thalamocortical neurons display suppressed burst-firing due to an enhanced Ih current in a genetic model of absence epilepsy. Pflügers Archiv, 467, 1367–1382.

    Article  CAS  PubMed  Google Scholar 

  • Chan, C. S., Guzman, J. N., Ilijic, E., Mercer, J. N., Rick, C., Tkatch, T., Meredith, G. E., & Surmeier, D. J. (2007). ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature, 447, 1081–1086.

    Article  CAS  PubMed  Google Scholar 

  • Chandra, K. S., & Ramesh, G. (2013). The fourth-generation calcium channel blocker: Cilnidipine. Indian Heart Journal, 65, 691–695.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cheong, E., & Shin, H. S. (2013). T-type Ca2+ channels in normal and abnormal brain functions. Physiological Reviews, 93, 961–992.

    Article  CAS  PubMed  Google Scholar 

  • Cleland, J. G., Teerlink, J. R., Senior, R., Nifontov, E. M., Mc Murray, J. J., Lang, C. C., Tsyrlin, V. A., Greenberg, B. H., Mayet, J., Francis, D. P., Shaburishvili, T., Monaghan, M., Saltzberg, M., Neyses, L., Wasserman, S. M., Lee, J. H., Saikali, K. G., Clarke, C. P., Goldman, J. H., … Malik, F. I. (2011). The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: A double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet, 378, 676–683.

    Article  CAS  PubMed  Google Scholar 

  • Dahlhamer, J., Lucas, J., Zelaya, C., Nahin, R., Mackey, S., DeBar, L., Kerns, R., Von Korff, M., Porter, L., & Helmick, C. (2018). Prevalence of chronic pain and high-impact chronic pain among adults – United States, 2016. MMWR. Morbidity and Mortality Weekly Report, 67(36), 1001–1006. https://doi.org/10.15585/mmwr.mm6736a2

  • Deer, T. R., Pope, J. E., Hanes, M. C., & McDowell, G. C. (2019). Intrathecal therapy for chronic pain: A review of morphine and ziconotide as firstline options. Pain Medicine, 20, 784–798.

    Article  PubMed  Google Scholar 

  • Derry, S., Bell, R. F., Straube, S., Wiffen, P. J., Aldington, D., & Moore, R. A. (2019). Pregabalin for neuropathic pain in adults. Cochrane Database of Systemic Reviews 2019, 2019(1), Art. No.:CD007076.

    Google Scholar 

  • Deuschl, G., & Elble, R. (2009). Essential tremor—Neurodegenerative or nondegenerative disease towards a working definition of ET. Movement Disorders, 24, 2033–2041.

    Article  PubMed  Google Scholar 

  • Dong, W., **, S. C., Allocco, A., Zeng, X., Sheth, A. H., Panchagnula, S., et al. (2020). Exome sequencing implicates impaired GABA signaling and neuronal ion transport in trigeminal neuralgia. iScience, 23(10), 101552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DuBreuil, D. M., Lopez Soto, E. J., Daste, S., Meir, R., Li, D., Wainger, B., Fleischmann, A., & Lipscombe, D. (2021). Heat but not mechanical hypersensitivity depends on voltage-gated CaV2.2 calcium channel activity in peripheral axon terminals innervating skin. The Journal of Neuroscience, 41, 7546–7560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elwes, R. D., & Binnie, C. D. (1996). Clinical pharmacokinetics of newer antiepileptic drugs. Lamotrigine, vigabatrin, gabapentin and oxcarbazepine. Clinical Pharmacokinetics, 30, 403–415.

    Article  CAS  PubMed  Google Scholar 

  • Evangelou, E., Warren, H. R., Mosen-Ansorena, D., Mifsud, B., Pazoki, R., Gao, H., Ntritsos, G., Dimou, N., Cabrera, C. P., Karaman, I., Ng, F. L., Evangelou, M., Witkowska, K., Tzanis, E., Hellwege, J. N., Giri, A., Velez Edwards, D. R., Sun, Y. V., Cho, K., et al. (2018). Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nature Genetics, 50, 1412–1425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fearnley, J. M., & Lees, A. J. (1991). Ageing and Parkinson’s disease: Substantia nigra regional selectivity. Brain, 114(Pt 5), 2283–2301.

    Article  PubMed  Google Scholar 

  • Field, M. J., Cox, P. J., Stott, E., Melrose, H., Offord, J., Su, T. Z., Bramwell, S., Corradini, L., England, S., Winks, J., Kinloch, R. A., Hendrich, J., Dolphin, A. C., Webb, T., & Williams, D. (2006). Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proceedings of the National Academy of Sciences of the United States of America, 103, 17537–17542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fleckenstein, A., Fleckenstein-Grun, G., Frey, M., & Thimm, F. (1990). Experimental antiarteriosclerotic effects of calcium antagonists. Journal of Clinical Pharmacology, 30, 151–154.

    Article  CAS  PubMed  Google Scholar 

  • Fujii, S., Kameyama, K., Hosono, M., Hayashi, Y., & Kitamura, K. (1997). Effect of cilnidipine, a novel dihydropyridine Ca++-channel antagonist, on N-type Ca++ channel in rat dorsal root ganglion neurons. The Journal of Pharmacology and Experimental Therapeutics, 280, 1184–1191.

    CAS  PubMed  Google Scholar 

  • Fujimura, K., & Matsuda, Y. (1989). Autogenous oscillatory potentials in neurons of the guinea pig substantia nigra pars compacta in vitro. Neuroscience Letters, 104, 53–57.

    Article  CAS  PubMed  Google Scholar 

  • Furberg, C. D., Psaty, B. M., & Meyer, J. V. (1995). Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation, 92, 1326–1331.

    Article  CAS  PubMed  Google Scholar 

  • Gakenheimer-Smith, L., Meyers, L., Lundahl, D., Menon, S. C., Bunch, T. J., Sawyer, B. L., Tristani-Firouzi, M., & Etheridge, S. P. (2021). Expanding the phenotype of CACNA1C mutation disorders. Molecular Genetics & Genomic Medicine, 9, e1673.

    Article  CAS  Google Scholar 

  • Gao, S., Yao, X., & Yan, N. (2021). Structure of human Cav2.2 channel blocked by the painkiller ziconotide. Nature, 596, 143–147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garrison, N. A., Hudson, M., Ballantyne, L. L., Garba, I., Martinez, A., Taualii, M., Arbour, L., Caron, N. R., & Rainie, S. C. (2019). Genomic research through an indigenous lens: Understanding the expectations. Annual Review of Genomics and Human Genetics, 20, 495–517.

    Article  CAS  PubMed  Google Scholar 

  • Gee, N. S., Brown, J. P., Dissanayake, V. U., Offord, J., Thurlow, R., & Woodruff, G. N. (1996). The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. The Journal of Biological Chemistry, 271, 5768–5776.

    Article  CAS  PubMed  Google Scholar 

  • Gironell, A., & Marin-Lahoz, J. (2016). Ethosuximide for essential tremor: An open-label trial. Tremor and Other Hyperkinetic Movements (N Y), 6, 378.

    Article  Google Scholar 

  • Gohil, K., Bell, J. R., Ramachandran, J., & Miljanich, G. P. (1994). Neuroanatomical distribution of receptors for a novel voltage-sensitive calcium-channel antagonist, SNX-230 (omega-conopeptide MVIIC). Brain Research, 653, 258–266.

    Article  CAS  PubMed  Google Scholar 

  • Gouel, F., Rolland, A. S., Devedjian, J. C., Burnouf, T., & Devos, D. (2019). Past and future of neurotrophic growth factors therapies in ALS: From single neurotrophic growth factor to stem cells and human platelet lysates. Frontiers in Neurology, 10, 835.

    Article  PubMed  PubMed Central  Google Scholar 

  • Grace, A. A., & Onn, S. P. (1989). Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro. The Journal of Neuroscience, 9, 3463–3481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gulsuner, S., Walsh, T., Watts, A. C., Lee, M. K., Thornton, A. M., Casadei, S., Rippey, C., Shahin, H., Consortium on the Genetics of S, Group PS, Nimgaonkar, V. L., Go, R. C., Savage, R. M., Swerdlow, N. R., Gur, R. E., Braff, D. L., King, M. C., & McClellan, J. M. (2013). Spatial and temporal map** of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell, 154, 518–529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guzman, J. N., Sanchez-Padilla, J., Wokosin, D., Kondapalli, J., Ilijic, E., Schumacker, P. T., & Surmeier, D. J. (2010). Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature, 468, 696–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Handforth, A., Homanics, G. E., Covey, D. F., Krishnan, K., Lee, J. Y., Sakimura, K., Martin, F. C., & Quesada, A. (2010). T-type calcium channel antagonists suppress tremor in two mouse models of essential tremor. Neuropharmacology, 59, 380–387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hara, K., & Sata, T. (2007). Inhibitory effect of gabapentin on N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Acta Anaesthesiologica Scandinavica, 51, 122–128.

    Article  CAS  PubMed  Google Scholar 

  • Hausmann, S. B., Vargas, A. M., Mathis, A., & Mathis, M. W. (2021). Measuring and modeling the motor system with machine learning. Current Opinion in Neurobiology, 70, 11–23.

    Article  CAS  PubMed  Google Scholar 

  • Hendrich, J., Van Minh, A. T., Heblich, F., Nieto-Rostro, M., Watschinger, K., Striessnig, J., Wratten, J., Davies, A., & Dolphin, A. C. (2008). Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin. Proceedings of the National Academy of Sciences of the United States of America, 105, 3628–3633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hou, L., Li, Q., Jiang, L., Qiu, H., Geng, C., Hong, J. S., Li, H., & Wang, Q. (2018). Hypertension and diagnosis of Parkinson’s disease: A meta-analysis of Cohort studies. Frontiers in Neurology, 9, 162.

    Article  PubMed  PubMed Central  Google Scholar 

  • Huguenard, J. R. (1996). Low-threshold calcium currents in central nervous system neurons. Annual Review of Physiology, 58, 329–348.

    Article  CAS  PubMed  Google Scholar 

  • Iannetti, G. D., Zambreanu, L., Wise, R. G., Buchanan, T. J., Huggins, J. P., Smart, T. S., Vennart, W., & Tracey, I. (2005). Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans. Proceedings of the National Academy of Sciences of the United States of America, 102, 18195–18200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ilijic, E., Guzman, J. N., & Surmeier, D. J. (2011). The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson’s disease. Neurobiology of Disease, 43, 364–371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ivanov, S. V., Ward, J. M., Tessarollo, L., McAreavey, D., Sachdev, V., Fananapazir, L., Banks, M. K., Morris, N., Djurickovic, D., Devor-Henneman, D. E., Wei, M. H., Alvord, G. W., Gao, B., Richardson, J. A., Minna, J. D., Rogawski, M. A., & Lerman, M. I. (2004). Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene. The American Journal of Pathology, 165, 1007–1018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwaki, H., Leonard, H. L., Makarious, M. B., Bookman, M., Landin, B., Vismer, D., Casey, B., Gibbs, J. R., Hernandez, D. G., Blauwendraat, C., Vitale, D., Song, Y., Kumar, D., Dalgard, C. L., Sadeghi, M., Dong, X., Misquitta, L., Scholz, S. W., Scherzer, C. R., … Uniformed Services University of the Health Sciences A, Group APWGSW and consortium AP. (2021). Accelerating medicines partnership: Parkinson’s disease. Genetic resource. Movement Disorders, 36, 1795–1804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jensen, A. A., Mosbacher, J., Elg, S., Lingenhoehl, K., Lohmann, T., Johansen, T. N., Abrahamsen, B., Mattsson, J. P., Lehmann, A., Bettler, B., & Brauner-Osborne, H. (2002). The anticonvulsant gabapentin (neurontin) does not act through gamma-aminobutyric acid-B receptors. Molecular Pharmacology, 61, 1377–1384.

    Article  CAS  PubMed  Google Scholar 

  • Jones, A. V., Hockley, J. R. F., Hyde, C., Gorman, D., Sredic-Rhodes, A., Bilsland, J., McMurray, G., Furlotte, N. A., Hu, Y., Hinds, D. A., Cox, P. J., & Scollen, S. (2016). Genome-wide association analysis of pain severity in dysmenorrhea identifies association at chromosome 1p13.2, near the nerve growth factor locus. Pain, 157, 2571–2581.

    Article  PubMed  PubMed Central  Google Scholar 

  • Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alfoldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., Gauthier, L. D., Brand, H., Solomonson, M., Watts, N. A., Rhodes, D., Singer-Berk, M., England, E. M., Seaby, E. G., Kosmicki, J. A., … MacArthur, D. G. (2020). The mutational constraint spectrum quantified from variation in 141,456 humans. Nature, 581, 434–443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kazda, S. (1991). The story of nifedipine. In P. R. Lichtlen & A. Reale (Eds.), Adalat. Springer. https://doi.org/10.1007/978-3-642-85498-9_3

    Chapter  Google Scholar 

  • Kazda, S., Garthoff, B., Dycka, J., & Iwai, J. (1982). Prevention of malignant hypertension in salt loaded “S” Dahl rats with the calcium antagonist nifedipine. Clinical and Experimental Hypertension. Part A, 4, 1231–1241.

    CAS  Google Scholar 

  • Kress, H. G., Simpson, K. H., Marchettini, P., Ver Donck, A., & Varrassi, G. (2009). Intrathecal therapy: what has changed with the introduction of ziconotide. Pain Practice, 9, 338–347. https://doi.org/10.1111/j.1533-2500.2009.00308.x

  • King, E. A., Davis, J. W., & Degner, J. F. (2019). Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. PLoS Genetics, 15, e1008489.

    Article  PubMed  PubMed Central  Google Scholar 

  • Koschak, A., Reimer, D., Huber, I., Grabner, M., Glossmann, H., Engel, J., & Striessnig, J. (2001). alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages. The Journal of Biological Chemistry, 276, 22100–22106.

    Article  CAS  PubMed  Google Scholar 

  • Lam, M., Chen, C. Y., Li, Z., Martin, A. R., Bryois, J., Ma, X., Gaspar, H., Ikeda, M., Benyamin, B., Brown, B. C., Liu, R., Zhou, W., Guan, L., Kamatani, Y., Kim, S. W., Kubo, M., Kusumawardhani, A., Liu, C. M., Ma, H., … Huang, H. (2019). Comparative genetic architectures of schizophrenia in East Asian and European populations. Nature Genetics, 51, 1670–1678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lambrechts, D., Storkebaum, E., Morimoto, M., Del-Favero, J., Desmet, F., Marklund, S. L., Wyns, S., Thijs, V., Andersson, J., van Marion, I., Al-Chalabi, A., Bornes, S., Musson, R., Hansen, V., Beckman, L., Adolfsson, R., Pall, H. S., Prats, H., Vermeire, S., … Carmeliet, P. (2003). VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genetics, 34, 383–394.

    Article  CAS  PubMed  Google Scholar 

  • Lanneau, C., Green, A., Hirst, W. D., Wise, A., Brown, J. T., Donnier, E., Charles, K. J., Wood, M., Davies, C. H., & Pangalos, M. N. (2001). Gabapentin is not a GABAB receptor agonist. Neuropharmacology, 41, 965–975.

    Article  CAS  PubMed  Google Scholar 

  • Lee, M. S., Newbold, E. J., & Papapetropoulos, S. (2019). Selective T-type calcium channel modulator CX-8998 fully suppresses seizures in the GAERS genetic model of epilepsy at human achievable concentrations (P1.5-026). Neurology, 92(15 Suppl), P1.5-026.

    Google Scholar 

  • Legge, S. E., Santoro, M. L., Periyasamy, S., Okewole, A., Arsalan, A., & Kowalec, K. (2021). Genetic architecture of schizophrenia: A review of major advancements. Psychological Medicine, 51, 2168–2177.

    Article  PubMed  Google Scholar 

  • Lewiecki, E. M. (2020). Romosozumab, clinical trials, and real-world care of patients with osteoporosis. The Annals of Translational Medicine, 8, 974.

    Article  PubMed  Google Scholar 

  • Li, S., DeLisi, L. E., & McDonough, S. I. (2021). Rare germline variants in individuals diagnosed with schizophrenia within multiplex families. Psychiatry Research, 303, 114038.

    Article  CAS  PubMed  Google Scholar 

  • Lichtlen, P. R., Hugenholtz, P. G., Rafflenbeul, W., Hecker, H., Jost, S., Nikutta, P., & Deckers, J. W. (1990). Retardation of coronary artery disease in humans by the calcium-channel blocker nifedipine: Results of the INTACT study (International Nifedipine Trial on Antiatherosclerotic Therapy). Cardiovascular Drugs and Therapy, 4(Suppl 5), 1047–1068.

    Article  PubMed  Google Scholar 

  • Lin, C. Y., Louis, E. D., Faust, P. L., Koeppen, A. H., Vonsattel, J. P., & Kuo, S. H. (2014). Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain, 137, 3149–3159.

    Article  PubMed  PubMed Central  Google Scholar 

  • Luckhaus, G., Nash, G., Garthoff, B., Kazda, S., & Feller, W. (1985). Healing of malignant hypertensive arteriopathy in Dahl rats by nifedipine. Arzneimittel-Forschung, 35, 115–121.

    CAS  PubMed  Google Scholar 

  • Malmberg, A. B., & Yaksh, T. L. (1994). Voltage-sensitive calcium channels in spinal nociceptive processing: Blockade of N- and P-type channels inhibits formalin-induced nociception. The Journal of Neuroscience, 14, 4882–4890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maneuf, Y. P., Luo, Z. D., & Lee, K. (2006). alpha2delta and the mechanism of action of gabapentin in the treatment of pain. Seminars in Cell & Developmental Biology, 17, 565–570.

    Article  CAS  Google Scholar 

  • Marais, E., Klugbauer, N., & Hofmann, F. (2001). Calcium channel alpha(2)delta subunits-structure and gabapentin binding. Molecular Pharmacology, 59, 1243–1248.

    Article  CAS  PubMed  Google Scholar 

  • Martin, D. J., McClelland, D., Herd, M. B., Sutton, K. G., Hall, M. D., Lee, K., Pinnock, R. D., & Scott, R. H. (2002). Gabapentin-mediated inhibition of voltage-activated Ca2+ channel currents in cultured sensory neurones is dependent on culture conditions and channel subunit expression. Neuropharmacology, 42, 353–366.

    Article  CAS  PubMed  Google Scholar 

  • McDonough, S. I. (2013). Calcium ion channels: Challenges and successes in drug discovery. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling, 2(2), 85–104. https://doi.org/10.1002/wmts.71

    Article  CAS  Google Scholar 

  • McDowell, G. C., Saulino, M. F., Wallace, M., Grigsby, E. J., Rauck, R. L., Kim, P., Vanhove, G. F., Ryan, R., Huang, I. Z., & Deer, T. (2020). Effectiveness and safety of intrathecal ziconotide: Final results of the patient registry of intrathecal ziconotide management (PRIZM). Pain Medicine, 21, 2925–2938.

    Article  PubMed  Google Scholar 

  • McIntosh, A. M., Hall, L. S., Zeng, Y., Adams, M. J., Gibson, J., Wigmore, E., Hagenaars, S. P., Davies, G., Fernandez-Pujals, A. M., Campbell, A. I., Clarke, T. K., Hayward, C., Haley, C. S., Porteous, D. J., Deary, I. J., Smith, D. J., Nicholl, B. I., Hinds, D. A., Jones, A. V., … Hocking, L. J. (2016). Genetic and environmental risk for chronic pain and the contribution of risk variants for major depressive disorder: A family-based mixed-model analysis. PLoS Medicine, 13, e1002090.

    Article  PubMed  PubMed Central  Google Scholar 

  • McLean, M. J. (1995). “Gabapentin” Epilepsia 36(s2) S73–S86. https://doi.org/10.1111/j.1528-1157.1995.tb06001.x

  • Miljanich, G. P. (2004). Ziconotide: Neuronal calcium channel blocker for treating severe chronic pain. Current Medicinal Chemistry, 11, 3029–3040.

    Article  CAS  PubMed  Google Scholar 

  • Mohammed, S. I., Eldabe, S., Simpson, K. H., Brookes, M., Madzinga, G., Gulve, A., Baranidharan, G., Radford, H., Crowther, T., Buchser, E., Perruchoud, C., & Batterham, A. M. (2013). Bolus intrathecal injection of ziconotide (Prialt(R)) to evaluate the option of continuous administration via an implanted intrathecal drug delivery (ITDD) system: A Pilot study. Neuromodulation, 16, 576–581; discussion 582.

    Article  PubMed  Google Scholar 

  • Monje, M., Borniger, J. C., D’Silva, N. J., Deneen, B., Dirks, P. B., Fattahi, F., Frenette, P. S., Garzia, L., Gutmann, D. H., Hanahan, D., Hervey-Jumper, S. L., Hondermarck, H., Hurov, J. B., Kepecs, A., Knox, S. M., Lloyd, A. C., Magnon, C., Saloman, J. L., Segal, R. A., … Winkler, F. (2020). Roadmap for the emerging field of cancer neuroscience. Cell, 181, 219–222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mori, Y., Nishida, M., Shimizu, S., Ishii, M., Yoshinaga, T., Ino, M., Sawada, K., & Niidome, T. (2002). Ca(2+) channel alpha(1B) subunit (Ca(V) 2.2) knockout mouse reveals a predominant role of N-type channels in the sympathetic regulation of the circulatory system. Trends in Cardiovascular Medicine, 12, 270–275.

    Article  CAS  PubMed  Google Scholar 

  • Mullard, A. (2019). Machine learning brings cell imaging promises into focus. Nature Reviews. Drug Discovery, 18, 653–655.

    Article  CAS  PubMed  Google Scholar 

  • Nalls, M. A., Blauwendraat, C., Vallerga, C. L., Heilbron, K., Bandres-Ciga, S., Chang, D., Tan, M., Kia, D. A., Noyce, A. J., Xue, A., Bras, J., Young, E., von Coelln, R., Simon-Sanchez, J., Schulte, C., Sharma, M., Krohn, L., Pihlstrom, L., Siitonen, A., … Me Research T, System Genomics of Parkinson’s Disease C and International Parkinson’s Disease Genomics C. (2019). Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: A meta-analysis of genome-wide association studies. Lancet Neurology, 18, 1091–1102.

    Article  CAS  PubMed  Google Scholar 

  • Nam, G. (2018). T-type calcium channel blockers: A patent review (2012-2018). Expert Opinion on Therapeutic Patents, 28, 883–901.

    Article  CAS  PubMed  Google Scholar 

  • Ng, G. Y., Bertrand, S., Sullivan, R., Ethier, N., Wang, J., Yergey, J., Belley, M., Trimble, L., Bateman, K., Alder, L., Smith, A., McKernan, R., Metters, K., O’Neill, G. P., Lacaille, J. C., & Hebert, T. E. (2001). Gamma-aminobutyric acid type B receptors with specific heterodimer composition and postsynaptic actions in hippocampal neurons are targets of anticonvulsant gabapentin action. Molecular Pharmacology, 59, 144–152.

    Article  CAS  PubMed  Google Scholar 

  • Olivera, B. M. (2021). A serendipitous path to pharmacology. Annual Review of Pharmacology and Toxicology, 61, 9–23.

    Article  CAS  PubMed  Google Scholar 

  • Ondo, W. G. (2020). Current and emerging treatments of essential tremor. Neurologic Clinics, 38, 309–323.

    Article  PubMed  Google Scholar 

  • Ortner, N. J., & Striessnig, J. (2016). L-type calcium channels as drug targets in CNS disorders. Channels (Austin, Tex.), 10, 7–13.

    Article  Google Scholar 

  • Papapetropoulos, S., Lee, M. S., Versavel, S., Newbold, E., **nah, H. A., Pahwa, R., Lyons, K. E., Elble, R., Ondo, W., Zesiewicz, T., Hedera, P., Handforth, A., Elder, J., & Versavel, M. (2021). A phase 2 proof-of-concept, randomized, placebo-controlled trial of CX-8998 in essential tremor. Movement Disorders, 36, 1944–1949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pardinas, A. F., Holmans, P., Pocklington, A. J., Escott-Price, V., Ripke, S., Carrera, N., Legge, S. E., Bishop, S., Cameron, D., Hamshere, M. L., Han, J., Hubbard, L., Lynham, A., Mantripragada, K., Rees, E., MacCabe, J. H., McCarroll, S. A., Baune, B. T., Breen, G., … Walters, J. T. R. (2018). Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nature Genetics, 50, 381–389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parkinson Study Group S-PDIIII. (2020). Isradipine versus placebo in early Parkinson disease: A randomized trial. Annals of Internal Medicine, 172, 591–598.

    Article  Google Scholar 

  • Peckham, A. M., Evoy, K. E., Ochs, L., & Covvey, J. R. (2018). Gabapentin for off-label use: Evidence-based or cause for concern? Substance Abuse, 12, 1178221818801311.

    PubMed  PubMed Central  Google Scholar 

  • Perucca, E. (2006). Clinically relevant drug interactions with antiepileptic drugs. The British Journal of Clinical Pharmacology, 61(3), 246–255.

    Article  CAS  PubMed  Google Scholar 

  • Planelles-Herrero, V. J., Hartman, J. J., Robert-Paganin, J., Malik, F. I., & Houdusse, A. (2017). Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil. Nature Communications, 8, 190.

    Article  PubMed  PubMed Central  Google Scholar 

  • Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O’Dushlaine, C., Chambert, K., Bergen, S. E., Kahler, A., Duncan, L., Stahl, E., Genovese, G., Fernandez, E., Collins, M. O., Komiyama, N. H., Choudhary, J. S., Magnusson, P. K., Banks, E., … Sklar, P. (2014). A polygenic burden of rare disruptive mutations in schizophrenia. Nature, 506, 185–190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rauck, R. L., Wallace, M. S., Leong, M. S., Minehart, M., Webster, L. R., Charapata, S. G., Abraham, J. E., Buffington, D. E., Ellis, D., Kartzinel, R., & Ziconotide 301 Study G. (2006). A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. Journal of Pain and Symptom Management, 31, 393–406.

    Article  CAS  PubMed  Google Scholar 

  • Sabatine, M. S., Wiviott, S. D., Im, K., Murphy, S. A., & Giugliano, R. P. (2018). Efficacy and safety of further lowering of low-density lipoprotein cholesterol in patients starting with very low levels: A meta-analysis. JAMA Cardiology, 3, 823–828.

    Article  PubMed  PubMed Central  Google Scholar 

  • Schulze-Bonhage, A. (2013). Pharmacokinetic and pharmacodynamic profile of pregabalin and its role in the treatment of epilepsy. Expert Opinion on Drug Metabolism & Toxicology, 9, 105–115.

    Article  CAS  Google Scholar 

  • Scott, S., Kranz, J. E., Cole, J., Lincecum, J. M., Thompson, K., Kelly, N., Bostrom, A., Theodoss, J., Al-Nakhala, B. M., Vieira, F. G., Ramasubbu, J., & Heywood, J. A. (2008). Design, power, and interpretation of studies in the standard murine model of ALS. Amyotrophic Lateral Sclerosis, 9, 4–15.

    Article  CAS  PubMed  Google Scholar 

  • Shipe, W. D., Barrow, J. C., Yang, Z. Q., Lindsley, C. W., Yang, F. V., Schlegel, K. A., Shu, Y., Rittle, K. E., Bock, M. G., Hartman, G. D., Tang, C., Ballard, J. E., Kuo, Y., Adarayan, E. D., Prueksaritanont, T., Zrada, M. M., Uebele, V. N., Nuss, C. E., Connolly, T. M., … Renger, J. J. (2008). Design, synthesis, and evaluation of a novel 4-aminomethyl-4-fluoropiperidine as a T-type Ca2+ channel antagonist. Journal of Medicinal Chemistry, 51, 3692–3695.

    Article  CAS  PubMed  Google Scholar 

  • Silverman, R. B. (2008). From basic science to blockbuster drug: The discovery of Lyrica. Angewandte Chemie, 47(19), 3500–3504.

    Article  CAS  PubMed  Google Scholar 

  • Silverman, R. B., Andruszkiewicz, R., Nanavati, S. M., Taylor, C. P., & Vartanian, M. G. (1991). 3-Alkyl-4-aminobutyric acids: The first class of anticonvulsant agents that activates L-glutamic acid decarboxylase. Journal of Medicinal Chemistry, 34, 2295–2298.

    Article  CAS  PubMed  Google Scholar 

  • Singh, K., Bijarnia-Mahay, S., Ramprasad, V. L., Puri, R. D., Nair, S., Sharda, S., Saxena, R., Kohli, S., Kulshreshtha, S., Ganguli, I., Gujral, K., & Verma, I. C. (2020). NGS-based expanded carrier screening for genetic disorders in North Indian population reveals unexpected results—A Pilot study. BMC Medical Genetics, 21, 216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Splawski, I., Timothy, K. W., Sharpe, L. M., Decher, N., Kumar, P., Bloise, R., Napolitano, C., Schwartz, P. J., Joseph, R. M., Condouris, K., Tager-Flusberg, H., Priori, S. G., Sanguinetti, M. C., & Keating, M. T. (2004). Cav1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell, 119(1), 19–31.

    Article  CAS  PubMed  Google Scholar 

  • Staats, P. S., Luthardt, F., Shipley, J., Jackson, C., & Fischer, K. (2001). Long-term intrathecal ziconotide therapy: A case study and discussion. Neuromodulation, 4, 121–126.

    Article  CAS  PubMed  Google Scholar 

  • Staats, P. S., Yearwood, T., Charapata, S. G., Presley, R. W., Wallace, M. S., Byas-Smith, M., Fisher, R., Bryce, D. A., Mangieri, E. A., Luther, R. R., Mayo, M., McGuire, D., & Ellis, D. (2004). Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: A randomized controlled trial. JAMA, 291, 63–70.

    Article  CAS  PubMed  Google Scholar 

  • Stewart, B. H., Kugler, A. R., Thompson, P. R., & Bockbrader, H. N. (1993). A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharmaceutical Research, 10, 276–281.

    Article  CAS  PubMed  Google Scholar 

  • Storkebaum, E., Lambrechts, D., Dewerchin, M., Moreno-Murciano, M. P., Appelmans, S., Oh, H., Van Damme, P., Rutten, B., Man, W. Y., De Mol, M., Wyns, S., Manka, D., Vermeulen, K., Van Den Bosch, L., Mertens, N., Schmitz, C., Robberecht, W., Conway, E. M., Collen, D., … Carmeliet, P. (2005). Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nature Neuroscience, 8, 85–92.

    Article  CAS  PubMed  Google Scholar 

  • Suman-Chauhan, N., Webdale, L., Hill, D. R., & Woodruff, G. N. (1993). Characterisation of [3H]gabapentin binding to a novel site in rat brain: Homogenate binding studies. European Journal of Pharmacology, 244, 293–301.

    Article  CAS  PubMed  Google Scholar 

  • Sun, J., & Triggle, D. J. (1995). Calcium channel antagonists: Cardiovascular selectivity of action. The Journal of Pharmacology and Experimental Therapeutics, 274(1), 419–426.

    CAS  PubMed  Google Scholar 

  • Szustakowski, J. D., Balasubramanian, S., Kvikstad, E., Khalid, S., Bronson, P. G., Sasson, A., Wong, E., Liu, D., Wade Davis, J., Haefliger, C., Katrina Loomis, A., Mikkilineni, R., Noh, H. J., Wadhawan, S., Bai, X., Hawes, A., Krasheninina, O., Ulloa, R., Lopez, A. E., … Team U-ER. (2021). Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank. Nature Genetics, 53, 942–948.

    Article  CAS  PubMed  Google Scholar 

  • Tassone, D. M., Boyce, E., Guyer, J., & Nuzum, D. (2007). Pregabalin: A novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clinical Therapeutics, 29, 26–48.

    Article  CAS  PubMed  Google Scholar 

  • Taylor, C. P., Vartanian, M. G., Andruszkiewicz, R., & Silverman, R. B. (1992). 3-alkyl GABA and 3-alkylglutamic acid analogues: Two new classes of anticonvulsant agents. Epilepsy Research, 11, 103–110.

    Article  CAS  PubMed  Google Scholar 

  • Teerlink, J. R., Felker, G. M., McMurray, J. J., Solomon, S. D., Adams, K. F., Jr., Cleland, J. G., Ezekowitz, J. A., Goudev, A., Macdonald, P., Metra, M., Mitrovic, V., Ponikowski, P., Serpytis, P., Spinar, J., Tomcsanyi, J., Vandekerckhove, H. J., Voors, A. A., Monsalvo, M. L., Johnston, J., … Investigators, C.-H. (2016). Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): A phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet, 388, 2895–2903.

    Article  CAS  PubMed  Google Scholar 

  • Teerlink, J. R., Diaz, R., Felker, G. M., McMurray, J. J. V., Metra, M., Solomon, S. D., Adams, K. F., Anand, I., Arias-Mendoza, A., Biering-Sorensen, T., Bohm, M., Bonderman, D., Cleland, J. G. F., Corbalan, R., Crespo-Leiro, M. G., Dahlstrom, U., Echeverria, L. E., Fang, J. C., Filippatos, G., … Investigators, G.-H. (2021). Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. The New England Journal of Medicine, 384, 105–116.

    Article  CAS  PubMed  Google Scholar 

  • Terwindt, G. M., Ophoff, R. A., Haan, J., Sandkuijl, L. A., Frants, R. R., & Ferrari, M. D. (1998). Migraine, ataxia and epilepsy: A challenging spectrum of genetically determined calcium channelopathies. Dutch Migraine Genetics Research Group. European Journal of Human Genetics, 6, 297–307.

    Article  CAS  PubMed  Google Scholar 

  • Thompson, J. C., Dunbar, E., & Laye, R. R. (2006). Treatment challenges and complications with ziconotide monotherapy in established pump patients. Pain Physician, 9, 147–152.

    PubMed  Google Scholar 

  • Thurlow, R. J., Brown, J. P., Gee, N. S., Hill, D. R., & Woodruff, G. N. (1993). [3H]gabapentin may label a system-L-like neutral amino acid carrier in brain. European Journal of Pharmacology, 247, 341–345.

    Article  CAS  PubMed  Google Scholar 

  • Toal, C. B., Meredith, P. A., & Elliott, H. L. (2012). Long-acting dihydropyridine calcium-channel blockers and sympathetic nervous system activity in hypertension: A literature review comparing amlodipine and nifedipine GITS. Blood Pressure, 21(Suppl 1), 3–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trujillano, D., Oprea, G. E., Schmitz, Y., Bertoli-Avella, A. M., Abou Jamra, R., & Rolfs, A. (2017). A comprehensive global genotype-phenotype database for rare diseases. Molecular Genetics & Genomic Medicine, 5, 66–75.

    Article  Google Scholar 

  • Tseng, Y. F., Lin, H. C., Chao, J. C., Hsu, C. Y., & Lin, H. L. (2021). Calcium Channel blockers are associated with reduced risk of Parkinson’s disease in patients with hypertension: A population-based retrospective Cohort study. Journal of the Neurological Sciences, 424, 117412.

    Article  CAS  PubMed  Google Scholar 

  • Uchida, S., Yamada, S., Nagai, K., Deguchi, Y., & Kimura, R. (1997). Brain pharmacokinetics and in vivo receptor binding of 1,4-dihydropyridine calcium channel antagonists. Life Sciences, 61, 2083–2090.

    Article  CAS  PubMed  Google Scholar 

  • Uneyama, H., Takahara, A., Dohmoto, H., Yoshimoto, R., Inoue, K., & Akaike, N. (1997). Blockade of N-type Ca2+ current by cilnidipine (FRC-8653) in acutely dissociated rat sympathetic neurones. British Journal of Pharmacology, 122, 37–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uneyama, H., Uchida, H., Konda, T., Yoshimoto, R., & Akaike, N. (1999). Selectivity of dihydropyridines for cardiac L-type and sympathetic N-type Ca2+ channels. European Journal of Pharmacology, 373, 93–100.

    Article  CAS  PubMed  Google Scholar 

  • Van Goor, F., Hadida, S., Grootenhuis, P. D., Burton, B., Cao, D., Neuberger, T., Turnbull, A., Singh, A., Joubran, J., Hazlewood, A., Zhou, J., McCartney, J., Arumugam, V., Decker, C., Yang, J., Young, C., Olson, E. R., Wine, J. J., Frizzell, R. A., … Negulescu, P. (2009). Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proceedings of the National Academy of Sciences of the United States of America, 106, 18825–18830.

    Article  PubMed  PubMed Central  Google Scholar 

  • Van Goor, F., Hadida, S., Grootenhuis, P. D. J., & Negulescu, P. A. (2011). Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. 108, 18843–18848. https://doi.org/10.1073/pnas.1105787108

  • Venuto, C. S., Yang, L., Javidnia, M., Oakes, D., Surmeier, D. J., & Simuni, T. (2021). Isradipine plasma pharmacokinetics and exposure-response in early Parkinson’s disease. Annals of Clinical Translational Neurology, 8(3), 603–612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verrey, F. (2003). System L: Heteromeric exchangers of large, neutral amino acids involved in directional transport. Pflügers Archiv, 445, 529–533.

    Article  CAS  PubMed  Google Scholar 

  • Vinuto, C. S., Yang, L. Javidnia, M., et al. (2021). Isradipine plasma pharmacokinetics and exposure-response in early Parkinson’s disease. Annals of Clinical and Translational Neurology, 8(3), 603–612. https://doi.org/10.1002/acn3.51300

  • Vitale, V., Battelli, D., Gasperoni, E., & Monachese, N. (2008). Intrathecal therapy with ziconotide: Clinical experience and considerations on its use. Minerva Anestesiologica, 74, 727–733.

    CAS  PubMed  Google Scholar 

  • Wallace, M. S., Charapata, S. G., Fisher, R., Byas-Smith, M., Staats, P. S., Mayo, M., McGuire, D., Ellis, D., & Ziconotide Nonmalignant Pain Study G. (2006). Intrathecal ziconotide in the treatment of chronic nonmalignant pain: A randomized, double-blind, placebo-controlled clinical trial. Neuromodulation, 9, 75–86.

    Article  PubMed  Google Scholar 

  • Wallace, M., Duan, R., Liu, W., Locke, C., & Nothaft, W. (2016). A randomized, double-blind, placebo-controlled, crossover study of the T-type calcium channel blocker ABT-639 in an intradermal capsaicin experimental pain model. Pain Medicine, 17(3), 551–560. https://doi.org/10.1093/pm/pnv068

  • Wang, A. L., Iadecola, C., & Wang, G. (2017). New generations of dihydropyridines for treatment of hypertension. Journal of Geriatric Cardiology, 14, 67–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Weiss, N., & Zamponi, G. W. (2020). Genetic T-type calcium channelopathies. Journal of Medical Genetics, 57, 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Xu, W., & Lipscombe, D. (2001). Neuronal Ca(V)1.3alpha(1) L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. The Journal of Neuroscience, 21, 5944–5951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu, J., Wang, D.-S., Bonin, R. P., Penna, A., Alavian-Ghavanini, A., Zurek, A. A., Rauw, G., Baker, G. B., Orser, B. A. (2019). “Gabapentin increases expression of δ subunit-containing GABAA receptors.” eBioMedicine, 42, 203–213.

    Google Scholar 

  • Zamponi, G. W. (2016). Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nature Reviews Drug Discovery, 15(1), 19–34.

    Article  CAS  PubMed  Google Scholar 

  • Zamponi, G. W., Feng, Z. P., Zhang, L., Pajouhesh, H., Ding, Y., Belardetti, F., Pajouhesh, H., Dolphin, D., Mitscher, L. A., & Snutch, T. P. (2009). Scaffold-based design and synthesis of potent N-type calcium channel blockers. Bioorganic & Medicinal Chemistry Letters, 19, 6467–6472.

    Article  CAS  Google Scholar 

  • Zamponi, G. W., Striessnig, J., Koschak, A., & Dolphin, A. C. (2015). The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacological Reviews, 67, 821–870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ziegler, D., Duan, W. R., An, G., Thomas, J. W., & Nothaft, W. (2015). A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain. Pain, 156, 2013–2020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Atalanta Therapeutics, Boston, MA, USA

    Stefan I. McDonough

Authors
  1. Stefan I. McDonough
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan I. McDonough .

Editor information

Editors and Affiliations

  1. Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada

    Gerald Werner Zamponi

  2. Department of Pathophysiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic

    Norbert Weiss

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

McDonough, S.I. (2022). From Calcium Channels to New Therapeutics. In: Zamponi, G.W., Weiss, N. (eds) Voltage-Gated Calcium Channels . Springer, Cham. https://doi.org/10.1007/978-3-031-08881-0_27

Download citation

Publish with us

Policies and ethics

Search

Navigation