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Genetic T-Type Calcium Channelopathies Norbert Weiss,‍ ‍ 1 Gerald W Zamponi‍ ‍ 2

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Genetic T-Type Calcium Channelopathies Norbert Weiss,‍ ‍ 1 Gerald W Zamponi‍ ‍ 2 Neurogenetics J Med Genet: first published as 10.1136/jmedgenet-2019-106163 on 19 June 2019. Downloaded from REVIEW Genetic T-type calcium channelopathies Norbert Weiss, 1 Gerald W Zamponi 2 1Institute of Organic Chemistry ABSTRact their electrophysiological and pharmacological and Biochemistry, Czech T-type channels are low-voltage-activated calcium properties. This heterogeneity is in part explained Academy of Sciences, Praha, Czech Republic channels that contribute to a variety of cellular and by the existence of three T-type channel isoforms, 2 12 13 14 Department of Physiology physiological functions, including neuronal excitability, Cav3.1, Cav3.2 and Cav3.3, which in humans and Pharmacology, Cumming hormone and neurotransmitter release as well as are encoded by the genes CACNA1G, CACNA1H School of Medicine, University developmental aspects. Several human conditions and CACNA1I, respectively (figure 1A). This diver- of Calgary, Calgary, Alberta, including epilepsy, autism spectrum disorders, sity is further enriched by the existence of several Canada schizophrenia, motor neuron disorders and aldosteronism channel splice variants. Indeed, alternative splicing have been traced to variations in genes encoding T-type of Ca 3.1,15–19 Ca 3.220–24 and Ca 3.325 26 contrib- Correspondence to v v v Dr Norbert Weiss, Institute channels. In this short review, we present the genetics of utes to increase the functional diversity of T-type of Organic Chemistry and T-type channels with an emphasis on structure-function channels and may also have important pathophysi- Biochemistry, Czech Academy of relationships and associated channelopathies. ological implications. Sciences, Praha 166 10, Czech T-type channels consist on a single Ca 3 pore- Republic; v weiss@ uochb. cas. cz and forming subunit that contains all the structural Dr Gerald W Zamponi, determinants of channel gating and ion selectivity Department of Physiology INTRODUCTION and permeability (for review see.27 The Ca 3 subunit and PharmacologyCumming v Low-voltage-activated Cav3 T-type channels are is a relatively large plasma membrane protein of School of Medicine, University members of the superfamily of voltage-gated about 260 kDa organised into four hydrophobic of Calgary, Calgary T2N 4N1, 1 Alberta, Canada; calcium channels. T-type channels are widely domains (DI to DIV), each of them made of six zamponi@ ucalgary. ca expressed throughout the nervous, the neuroen- transmembrane helices (S1 to S6) (figure 1B). The 2 docrine and the cardiovascular system and are voltage-sensing module of the channel is formed Received 20 March 2019 also found in several non-excitable tissues such as Revised 2 May 2019 by the positively charged arginine/lysine-rich S4 osteocytes,3 sperm cells4 and immune cells.5 6 The 28 Accepted 18 May 2019 segments, while the ion conductivity and selec- cellular and physiological processes in which T-type tivity lie on the re-entrant extracellular linkers channels are implicated depend primarily on the connecting S5 and S6 segments of each domain, tissue distribution of the channels. For instance, in so-called pore-forming loop (P loop).2 The four the central and peripheral nervous systems, T-type transmembrane domains are linked together channels play an essential role in shaping neuronal by several intracellular loops connecting the S6 excitability,7–9 whereas they contribute to the release 10 11 segment of the upstream domain to the S1 segment http://jmg.bmj.com/ of hormones in the neuroendocrine system. of the downstream domain, which in combination The essential role of T-type channels in human with the amino and carboxy termini provide hubs physiology is emphasised by the existence of chan- for channel regulation by a variety of signalling nelopathies which are disorders that are caused or molecules and other molecular partners including enhanced by mutations in genes that encode these the G-protein βγ-dimer,29 30 CaMKII,31 32 kelch- channels. Most of T-type channelopathies are trans- like 1,33 calcineurin,34 syntaxin-1A,35 stac1,36 37 38 39 mitted by recessive inheritance or appear sporadic. CACHD1, spectrin α/β and ankyrin B as well on September 29, 2021 by guest. Protected copyright. The clinical manifestations of these disorders as several ion channels.40 41 In addition, T-type depend primarily on dysfunctions of the biophys- channels undergo several post-translational modifi- ical characteristics and cell surface trafficking of the cations such as phosphorylation,42 ubiquitination43 channels and can lead to either gain-of-function or and glycosylation,44–49 which contribute to the loss-of-function. expression and activity of the channel. In this review, we present an overview of human The contribution of T-type channels in particular T-type channelopathies and their relationship with cellular processes is partly inherent to their unique the diversity, structure and function of T-type chan- electrophysiological properties. Voltage-dependent nels. This will be followed by the presentation of opening of T-type channels occurs at comparatively the various syndromes for which T-type channels © Author(s) (or their negative membrane potentials where calcium influx have been linked to, with an emphasis on the struc- employer(s)) 2019. Re-use contributes to the depolarisation of the plasma ture-function-pathogenicity relationship of mutant permitted under CC BY-NC. No membrane, therefore increasing the opening prob- commercial re-use. See rights Cav3 channels. and permissions. Published ability of voltage-gated sodium channels and the by BMJ. propensity of cells to fire action potentials. This DIVERSITY, STRUCTURE AND FUNCTION OF aspect is especially relevant in several central To cite: Weiss N, CA 3 CHANNELS neurons including thalamic and hippocampal cells Zamponi GW. J Med Genet V Epub ahead of print: [please Although T-type currents recorded from various where T-type channels are particularly abundant include Day Month Year]. native tissues present a common feature illus- in dendrites to enhance subthreshold postsynaptic doi:10.1136/ trated by a low-threshold of activation around potentials and facilitate the propagation of the jmedgenet-2019-106163 −55 mV, they also exhibit several differences in electrical signal to the cell body.50 Another way by Weiss N, Zamponi GW. J Med Genet 2019;0:1–10. doi:10.1136/jmedgenet-2019-106163 1 Neurogenetics J Med Genet: first published as 10.1136/jmedgenet-2019-106163 on 19 June 2019. Downloaded from Figure 1 Chromosomal location of human Cav3 channels and their membrane topology. (A) Chromosomal location of human CACNA1G, CACNA1H and CACNA1I genes encoding Cav3.1, Cav3.2 and Cav3.3 channels, respectively. (B) Secondary membrane topology of Cav3 depicting the main structural channel gating determinants. http://jmg.bmj.com/ which T-type channels contribute to neuronal excitability is by dysfunction associated with ageing.65 Mice lacking Cacna1h forming functional complexes with several types of voltage-acti- display abnormal coronary function,66 67 decreased suscepti- vated and calcium-activated potassium channels that allow these bility to cardiac hypertrophy68 and absence seizure,69 decreased channels to operate at subthreshold membrane potentials.51–55 peripheral pain signalling70 as well as several neurological symp- In addition, their fast recovery from inactivation allows T-type toms including elevated anxiety and impaired memory.71 72 Mice channels to generate calcium spikes on brief periods of hyperpo- lacking Cacna1I have provided important information on the 73 74 on September 29, 2021 by guest. Protected copyright. larisation, which leads to the firing of rebound burst of action implication of Cav3.3 channels in sleep rhythmogenesis. potentials that support various forms of neuronal rhythmogen- Finally, several studies from genetic knock out have uncovered a esis.56–59 Although a significant fraction of T-type channels is role for T-type channels in the control of myogenic tone.75 inactivated at most resting membrane potentials of nerve cells, Considering that the cellular and physiological functions in a small fraction remains open to support the passive influx of which T-type channels are implicated are directly dependent on calcium (termed window current due to the ‘window’ created their electrophysiological properties, it is anticipated that alter- by the overlap between the activation and inactivation curves of ation of channel gating caused by mutations will have deleterious the channels). In nerve cells, this window current has been impli- consequences. In the next section, we will cover the current cated in the generation of low frequency oscillations observed state of knowledge of T-type channelopathies and illustrate the during sleep patterns60 and is likely to play additional functions links between the structure-function of mutant channels and the especially in non-excitable cells. T-type channels also contribute pathophysiological features of the associated human syndromes. to several forms of synaptic plasticity.61 Finally, T-type channels are implicated in the low-threshold release of neurotransmitters and hormones, possibly by virtue of their functional coupling CACNA1H (CAV3.2) CHANNELOPATHIES with the vesicular release machinery.10 11 Genetic knockout in Idiopathic generalised epilepsy mice also provided insightful information on the physiolog- It is well established that T-type channels play an essential ical importance of T-type channels. For instance, knockout of role in the
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