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Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
SCA6 is caused by a mutation in the C-terminus of the a1A subunit of the P/Q-type VGCC. Numerous studies have attempted to determine how the polyglutamine expansion affects the properties of the P/Q-type calcium channel, and ultimately how a small polyglutamine expansion in a VGCC may lead to cell death. Unfortunately, these results appear highly variable and depend on which expression system and auxiliary VGCC subunits are used.
Epidemiology and impact of headache disorders
Published in Stephen D. Silberstein, Richard B. Upton, Peter J. Goadsby, Headache in Clinical Practice, 2018
Stephen D. Silberstein, Richard B. Upton, Peter J. Goadsby
The Dutch group has identified a neuronal calcium channel protein believed to be the product of the pathogenic gene on chromosome 19.94 This gene codes for the alpha-l-A subunit of a voltage gated P/Q type calcium channel (CACNAIA). Several different missense mutations have been identified in association with FHM.90,92,94
Migraine: Management and Treatment with Herbal Drugs
Published in Vikas Kumar, Addepalli Veeranjaneyulu, Herbs for Diabetes and Neurological Disease Management, 2018
Arulmozhi D. Kandasamy, Yogesh Anant Kulkarni, Addepalli Veeranjaneyulu, Ram S. Gaud
Migraine is best understood as primary disorder of pain.25 It is a form of neurovascular headache: a disorder in which neural events result in the dilation of blood vessels, which in turn, results in pain and further nerve activation.26 Migraine is not caused by primary vascular event. Migraine attacks are episodic and vary within and among the individuals. The variability is best explained by considering the biologic problem in migraine to be the dysfunction of an ion channel in the aminergic brain stem nuclei that normally modulates sensory input and exerts neural influences on cranial vessels.25 In patients with hemiplegic migraine, missense mutation in the a1 subunit of the voltage gated P/Q-type calcium channels has been identified.27 It is possible that other ion-channel mutations contribute to migraine without aura, since it is primarily patients of migraine with aura who have been linked to the familial hemiplegic migraine locus.28 Thus, it is possible that the aura of migraine is separate from the headache, with aura susceptibility genes as its determinant,25 the pain-associated features of migraine itself may be determined by another gene or genes.
Effect of anxiolytic drug silexan on sleep – a narrative review
Published in The World Journal of Biological Psychiatry, 2022
Erich Seifritz, Siegfried Kasper, Hans-Jürgen Möller, Hans-Peter Volz, Walter E. Müller, Anne Eckert, Martin Hatzinger
Anxiety and mood disorders have been associated pathophysiologically with an overreaching, situationally inadequate stress response of the central nervous system (Satpute et al. 2012). In an animal model, Schuwald et al. (2013) demonstrated that physiological concentrations of silexan in the nanomolar range, which correlate to the marketed dosage of 80 mg/d in humans, cause a potent inhibition of voltage dependent calcium channels (VOCCs) in synaptosomes, primary hippocampal neurons and stably overexpressing cell lines with some similarity to the effects observed for pregabalin. However, in contrast to pregabalin, silexan does not primarily interact with the α2δ subunit of P/Q-type calcium channels but reduces the calcium influx non-selectively through several different types of VOCCs (e.g. N-type, P/Q-type and T-type VOCCs). Preclinical studies indicate that an enhanced calcium influx through VOCCs may increase the release of neurotransmitters such as glutamate and norepinephrine (Musazzi et al. 2011) which play an important role in the pathogenesis of anxiety. The inhibition of VOCCs by silexan may thus have a normalising effect on hyperactive nerve cells and counteract symptomatic expressions like spinning thoughts and anxious moods.
Current challenges in the pathophysiology, diagnosis, and treatment of paroxysmal movement disorders
Published in Expert Review of Neurotherapeutics, 2021
Cécile Delorme, Camille Giron, David Bendetowicz, Aurélie Méneret, Louise-Laure Mariani, Emmanuel Roze
Paroxysmal dyskinesia can occasionally be part of the phenotype associated with calcium voltage-gated channel subunit alpha1 A (CACNA1A) [34] and potassium voltage-gated channel subfamily A member 1 (KCNA1) [35,p.1] pathogenic variants that are typically associated with episodic ataxia. Tottering mice exhibit paroxysmal dystonia due to a point mutation in the CACNA1A gene [36]. Their dystonia occurs as attacks superimposed on a baseline of mild ataxia. The mutation impairs activity of CaV2.1 (P/Q-type) calcium channels, and dystonic motor behavior arises from maladaptive plasticity involving secondary up-regulation of CaV1.2 (L-type) calcium channels in the cerebellum [37]. The dystonic episodes induce c-fos expression in the cerebellar circuitry including Purkinje cells, deep cerebellar nuclei, and postsynaptic targets of the deep nuclei, indicating an increased neuronal activity. Degeneration of the Purkinje cells eliminates dystonia and restores normal c-fos expression [38]. Lethargic mice carry a mutation in the calcium channel beta subunit 4 (CCHB4) gene, which encodes another calcium channel subunit. They exhibit mild ataxia and hypokinesia with intermittent attacks of dyskinetic movements[39] Surgical removal of the cerebellum worsens ataxia but eliminates paroxysmal dyskinesia in these mice [40].
Silexan in anxiety disorders: Clinical data and pharmacological background
Published in The World Journal of Biological Psychiatry, 2018
Siegfried Kasper, Walter E. Müller, Hans-Peter Volz, Hans-Jürgen Möller, Egon Koch, Angelika Dienel
Furthermore, the authors were able to show that Silexan bears some similarities with the established anxiolytic pregabalin as it non-selectively inhibits voltage-operated calcium channels (VOCCs) already at nanomolar concentrations. Silexan, however, does not primarily interact with the α2δ subunit of P/Q-type calcium channels, which is the binding site of pregabalin. Instead, Silexan non-selectively reduces the calcium influx through several different types of VOCCs (e.g. N-type, P/Q-type and T-type VOCCs). It has been speculated that under pathological conditions, such as anxiety or stress disorders, an enhanced Ca2+ influx through N-type and P/Q-type VOCCs may increase the release of neurotransmitters such as glutamate and norepinephrine (Musazzi et al. 2011; Kalk et al. 2011), which are involved in the pathogenesis of these diseases. By inhibiting VOCCs, Silexan may have a normalising effect on hyperactive nerve cells and counteract the symptomatic expressions such as spinning thoughts and anxious moods.