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      Botulinum Toxin Type A Possibly Affects Ca v3.2 Calcium Channel Subunit in Rats with Spinal Cord Injury-Induced Muscle Spasticity


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          Spinal cord injury (SCI) often causes muscle spasticity, which can be inhibited by using calcium channel blocker. Botulinum toxin type A (BoT-A) shows therapeutic efficacy on spasticity and may exert inhibitory effects on the calcium channel.


          A rat model with muscle spasticity was established after SCI via contusion and compression. Different concentrations (0, 1, 3 and 6 U/kg) of BoT-A Botox were injected in the extensor digitorum longus (EDL) muscles of the right hindlimb in the muscle spasticity model. The changes of muscle spasticity and calcium level in EDL muscles were measured after the establishment of SCI-induced spasticity. Ca v3.2 calcium channel subunit and its mutant (M1560V) were analyzed using Western blot before (input) or after immunoprecipitation with anti-FLAG antibody, and their currents were measured in motoneurons by using whole-cell voltage clamp recordings.


          SCI induced muscle spasticity, whereas calcium level in EDL muscles and expression of Ca v3.2 was increased in the SCI model when compared with the sham group (p < 0.05). BoT-A Botox treatment significantly reduced muscle spasticity and calcium level in EDL muscles and Ca v3.2 expression in a dose-dependent way (p < 0.05). The ratio of biotinylated to total Ca v3.2 was reduced in the mutant (M1560V) of Ca v3.2 and lower than that in the wild Ca v3.2. BoT-A Botox intervention also reduced the current values of calcium channel and the ratio in a dose-dependent way (p < 0.05).


          BoT-A Botox possibly attenuates SCI-induced muscle spasticity by affecting the expression of Ca v3.2 calcium channel subunit in the rat models. There may be multiple mechanisms for the function of BoT-A Botox. Further work is needed to be done to address these issues.

          Most cited references49

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          Molecular physiology of low-voltage-activated t-type calcium channels.

          T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the alpha1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.
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            Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

            Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1H M1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension. DOI: http://dx.doi.org/10.7554/eLife.06315.001
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              Regulation of neuronal activity by Cav3-Kv4 channel signaling complexes.

              Kv4 low voltage-activated A-type potassium channels are widely expressed in excitable cells, where they control action potential firing, dendritic activity and synaptic integration. Kv4 channels exist as a complex that includes K(+) channel-interacting proteins (KChIPs), which contain calcium-binding domains and therefore have the potential to confer calcium dependence on the Kv4 channel. We found that T-type calcium channels and Kv4 channels form a signaling complex in rat that efficiently couples calcium influx to KChIP3 to modulate Kv4 function. This interaction was critical for allowing Kv4 channels to function in the subthreshold membrane potential range to regulate neuronal firing properties. The widespread expression of these channels and accessory proteins indicates that the Cav3-Kv4 signaling complex is important for the function of a wide range of electrically excitable cells.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                28 July 2020
                : 14
                : 3029-3041
                [1 ]Department of Pain Medicine, The First Hospital of Jilin University , Changchun 130021, People’s Republic of China
                [2 ]Department of Neurologic Medicine, The First Hospital of Jilin University , Changchun 130021, People’s Republic of China
                [3 ]Department of Medicine and Pension, The First Hospital of Jilin University , Changchun 130021, People’s Republic of China
                Author notes
                Correspondence: Lijie Lv Department of Medicine and Pension, The First Hospital of Jilin University , No. 71 Xinmin Street, Changchun130021, People’s Republic of ChinaTel +86-431-88782032 Email lvlj1010@126.com
                © 2020 Ma et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                : 03 April 2020
                : 26 June 2020
                Page count
                Figures: 7, References: 55, Pages: 13
                Original Research

                Pharmacology & Pharmaceutical medicine
                botulinum toxin type a,muscle spasticity,cav3.2 calcium channel,rat model,spinal cord injuries


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