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The T-type calcium channel as a new therapeutic target for Parkinson’s disease

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Abstract

Parkinson’s disease (PD) is one of the most prevalent movement disorder caused by degeneration of the dopaminergic neurons in substantia nigra pars compacta. Deep brain stimulation (DBS) at the subthalamic nucleus (STN) has been a new and effective treatment of PD. It is interesting how a neurological disorder caused by the deficiency of a specific chemical substance (i.e., dopamine) from one site could be so successfully treated by a pure physical maneuver (i.e., DBS) at another site. STN neurons could discharge in the single-spike or the burst modes. A significant increase in STN burst discharges has been unequivocally observed in dopamine-deprived conditions such as PD, and was recently shown to have a direct causal relation with parkinsonian symptoms. The occurrence of burst discharges in STN requires enough available T-type Ca2+ currents, which could bring the relatively negative membrane potential to the threshold of firing Na+ spikes. DBS, by injection of negative currents into the extracellular space, most likely would depolarize the STN neuron and then inactivate the T-type Ca2+ channel. Burst discharges are thus decreased and parkinsonian locomotor deficits ameliorated. Conversely, injection of positive currents into STN itself could induce parkinsonian locomotor deficits in animals without dopaminergic lesions. Local application of T-type Ca2+ channel blockers into STN would also dramatically decrease the burst discharges and improve parkinsonian locomotor symptoms. Notably, zonisamide, which could inhibit T-type Ca2+ currents in STN, has been shown to benefit PD patients in a clinical trial. From the pathophysiological perspectives, PD can be viewed as a prototypical disorder of “brain arrhythmias”. Modulation of relevant ion channels by physical or chemical maneuvers may be important therapeutic considerations for PD and other diseases related to deranged neural rhythms.

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Acknowledgements

We thank Chen-Syuan Huang for the technical assistance. Our work in this field was supported by the National Science Council, Taiwan (grants NSC99-2311-B-182-001-MY3 and NSC102-2311-B-182-003 to Y.-C. Y., NSC 101-2314-B-002-133-MY3 to C.-H. T., and NSC100-2320-B-002-009-MY3 and NSC102-2321-B-002-058 to C.-C. K.) and by the Chang Gung Hospital, Taiwan (grants CMRPD3B0021-3 to Y.-C. Y.).

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  1. Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan

    Ya-Chin Yang

  2. Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan

    Ya-Chin Yang

  3. Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan

    Chun-Hwei Tai, Ming-Kai Pan & Chung-Chin Kuo

  4. Department of Physiology, National Taiwan University College of Medicine, No. 1, Jen-Ai Rd., 1st Section, Taipei, 100, Taiwan

    Ming-Kai Pan & Chung-Chin Kuo

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This article is published as part of the special issue on [T-type (Cav3) calcium channels in health and disease]

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Yang, YC., Tai, CH., Pan, MK. et al. The T-type calcium channel as a new therapeutic target for Parkinson’s disease. Pflugers Arch - Eur J Physiol 466, 747–755 (2014). https://doi.org/10.1007/s00424-014-1466-6

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