DOCSLIB.ORG

Restricting Calcium Currents Is Required for Correct Fiber Type

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Restricting Calcium Currents Is Required for Correct Fiber Type © 2016. Published by The Company of Biologists Ltd | Development (2016) 143, 1547-1559 doi:10.1242/dev.129676 RESEARCH ARTICLE Restricting calcium currents is required for correct fiber type specification in skeletal muscle Nasreen Sultana1, Beatrix Dienes2, Ariane Benedetti1, Petronel Tuluc3, Peter Szentesi2, Monika Sztretye2, Johannes Rainer4, Michael W. Hess5, Christoph Schwarzer6, Gerald J. Obermair1, Laszlo Csernoch2 and Bernhard E. Flucher1,* ABSTRACT CaV1.1 can directly activate opening of the RyR1. In mature Skeletal muscle excitation-contraction (EC) coupling is independent muscles, calcium is released from the sarcoplasmic reticulum (SR) of calcium influx. In fact, alternative splicing of the voltage-gated calcium stores, whereas calcium influx is dispensable for skeletal muscle EC coupling (Melzer et al., 1995). Actually, calcium calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Whether this is necessary for normal development currents through the major CaV1.1a splice variant are small and and function of muscle is not known. However, splicing defects that activate slowly, only at strong membrane depolarizations. cause aberrant expression of the calcium-conducting developmental Interestingly, during maturation of mammalian skeletal muscles activity-dependent calcium influx is actively suppressed by CaV1.1e splice variant correlate with muscle weakness in myotonic alternative splicing of CaV1.1. In fetal muscles, exclusion of exon dystrophy. Here, we deleted CaV1.1 (Cacna1s) exon 29 in mice. These mice displayed normal overall motor performance, although 29 produces a CaV1.1e channel variant that conducts sizable L-type grip force and voluntary running were reduced. Continued expression calcium currents and activates in parallel to SR calcium release at physiological voltages (Tuluc et al., 2009). However, after birth, the of the developmental CaV1.1e splice variant in adult mice caused increased calcium influx during EC coupling, altered calcium developmental CaV1.1e splice variant is almost completely replaced homeostasis, and spontaneous calcium sparklets in isolated by the adult, poorly conducting CaV1.1a splice variant that includes muscle fibers. Contractile force was reduced and endurance exon 29 (Flucher and Tuluc, 2011; Tang et al., 2012). Why calcium enhanced. Key regulators of fiber type specification were influx is present in developing muscle but is then curtailed in mature dysregulated and the fiber type composition was shifted toward skeletal muscles is not known. Conversely, it remains to be slower fibers. However, oxidative enzyme activity and mitochondrial determined whether continued expression of the calcium- content declined. These findings indicate that limiting calcium influx conducting CaV1.1e splice variant alters contractile properties of during skeletal muscle EC coupling is important for the secondary mature skeletal muscles. function of the calcium signal in the activity-dependent regulation of In addition to their primary role in EC coupling, activity-induced fiber type composition and to prevent muscle disease. calcium signals in skeletal muscle are important for maintaining calcium homeostasis and for the regulation of muscle growth and KEY WORDS: Voltage-gated calcium channel, Skeletal muscle differentiation. For example, calcium signals regulate the excitation-contraction coupling, Muscle fiber type specification, transcription of genes involved in the adaptive response to Mouse exercise (Bassel-Duby and Olson, 2006). Therefore, the tight control of calcium influx by alternative splicing of the CaV1.1 INTRODUCTION channel is probably important for tuning muscle function to varying Calcium is the principal second messenger regulating skeletal activity levels. Conversely, calcium influx through CaV1.1e muscle contraction, growth and differentiation. In excitation- channels in mature muscles might be harmful. Abnormal contraction (EC) coupling, cytoplasmic calcium levels are rapidly expression of the embryonic, calcium-conducting CaV1.1e splice increased in response to action potentials and the magnitude of these variant in myotonic dystrophy type 1 (DM1) patients correlates with calcium signals regulates the force of contraction. In skeletal their degree of muscle weakness (Tang et al., 2012). Moreover, muscle, voltage-gated calcium channels (CaV1.1) and calcium aberrant splicing of calcium channels and transporters in cultured release channels (type 1 ryanodine receptors, RyR1) are physically myotubes from DM1 patients leads to altered intracellular calcium coupled to one another so that voltage-dependent activation of signaling (Santoro et al., 2014), and experimentally induced skipping of exon 29 aggravated the disease phenotype in muscles 1Department of Physiology and Medical Physics, Medical University of a myotonia mouse model (Tang et al., 2012). Innsbruck, Innsbruck 6020, Austria. 2Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary. 3Department of To identify the physiological importance of curtailing calcium 4 Pharmacology, University of Innsbruck, Innsbruck 6020, Austria. Division of influx through CaV1.1 channels in adult skeletal muscle and to Molecular Pathophysiology, Biocenter, Medical University Innsbruck, Innsbruck reveal a possible involvement of aberrant calcium signaling in 6020, Austria. 5Division of Histology and Embryology, Medical University Innsbruck, Innsbruck 6020, Austria. 6Department of Pharmacology, Medical DM1, we generated a genetic mouse model in which exon 29 has University Innsbruck, Innsbruck 6020, Austria. been permanently deleted. As expected, skeletal muscles of ΔE29/ΔE29 CaV1.1 knockout mice experienced increased calcium *Author for correspondence ([email protected]) influx during EC coupling and at rest. In addition, their contractile This is an Open Access article distributed under the terms of the Creative Commons Attribution properties were altered, calcium-activated downstream regulators License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. were upregulated, and the fiber type composition was shifted towards slower fiber types. However, mitochondrial content and Received 11 August 2015; Accepted 29 February 2016 oxidative enzyme activity were reduced. Together, these findings DEVELOPMENT 1547 RESEARCH ARTICLE Development (2016) 143, 1547-1559 doi:10.1242/dev.129676 indicate that chronically increased calcium influx through the muscle strength. Endurance was tested by making the mice run on a developmental CaV1.1e isoform has little effect on EC coupling, but treadmill at accelerating speed until exhaustion. Overall motor disturbs the normal regulation of muscle fiber type composition. performance was examined with the Rotarod test. In none of these Furthermore, the increased calcium influx causes mitochondrial tests was a significant difference in the performance of wild-type, +/ΔE29 ΔE29/ΔE29 damage and may thus contribute to muscle wasting in DM1. heterozygous CaV1.1 and homozygous CaV1.1 mice Conversely, these results suggest that, during normal development, observed. However, directly measuring grip strength revealed that limiting L-type calcium currents is important to enable the proper the grip force of the front paws was significantly reduced in ΔE29/ΔE29 specification of fiber type composition and to protect the muscles homozygous CaV1.1 mice (Fig. 2D). Finally, voluntary from calcium-induced damage. running of the mice in a running wheel was recorded over the period of 7 days. Both the distance run and the duration the mice spent RESULTS running per day were significantly reduced in homozygous ΔE29/ΔE29 Selective deletion of CaV1.1 exon 29 prevents the CaV1.1 mice compared with wild-type controls (Fig. 2E). developmental switch from the CaV1.1e to the CaV1.1a These behavioral and functional analyses indicate that aberrant isoform expression of CaV1.1e alters muscle performance without causing In order to study the importance of the isoform switch from the severe motor deficits as assessed in tests that revealed the disease calcium-conducting developmental CaV1.1e splice variant to the phenotype in other DM mouse models (Gomes-Pereira et al., 2011). poorly conducting adult CaV1.1a splice variant we generated a Also, histological staining of muscle sections did not reveal an ΔE29/ΔE29 mouse model with a constitutive knockout of exon 29 of the CaV1.1 increase in centrally located nuclei in CaV1.1 muscles (Cacna1s) gene (Fig. 1A). We reasoned that because the short (Fig. S1B). transcript CaV1.1e is predominant during fetal development, ΔE29 CaV1.1 mice would develop normally up to birth, but that the Aberrant expression of the developmental CaV1.1e isoform aberrant continuing expression of the high-conductance in mature muscles alters the contractile properties of developmental calcium channel splice variant throughout isolated slow and fast muscles postnatal development and adult life would reveal any influence Because the reduced grip force and voluntary running indicated of the extra calcium influx on EC coupling and/or other calcium- altered muscle performance, we next determined the contractile mediated signaling processes regulating muscle growth and properties directly in isolated mouse muscles. The contractile force ΔE29 differentiation. Furthermore, the CaV1.1 mouse will expose of soleus and EDL muscles was
Load more

Recommended publications
  • Spectrum of CLCN1 Mutations in Patients with Myotonia Congenita in Northern Scandinavia
    European Journal of Human Genetics (2001) 9, 903 ± 909 ã 2001 Nature Publishing Group All rights reserved 1018-4813/01 $15.00 www.nature.com/ejhg ARTICLE Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia Chen Sun*,1, Lisbeth Tranebjñrg*,1, Torberg Torbergsen2,GoÈsta Holmgren3 and Marijke Van Ghelue1,4 1Department of Medical Genetics, University Hospital of Tromsù, Tromsù, Norway; 2Department of Neurology, University Hospital of Tromsù, Tromsù, Norway; 3Department of Clinical Genetics, University Hospital of UmeaÊ, UmeaÊ,Sweden;4Department of Biochemistry, Section Molecular Biology, University of Tromsù, Tromsù, Norway Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C4T) were novel while the others (IVS1+3A4T, 979G4A, F413C, A531V, and R894X) have been reported previously.
    [Show full text]
  • Unnatural Verticilide Enantiomer Inhibits Type 2 Ryanodine Receptor-Mediated Calcium Leak and Is Antiarrhythmic
    Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic Suzanne M. Batistea,1, Daniel J. Blackwellb,1, Kyungsoo Kimb,1, Dmytro O. Kryshtalb, Nieves Gomez-Hurtadob, Robyn T. Rebbeckc, Razvan L. Corneac, Jeffrey N. Johnstona,2, and Bjorn C. Knollmannb,2 aDepartment of Chemistry, Vanderbilt University, Nashville, TN 37235; bDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; and cDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455 Edited by Dale L. Boger, The Scripps Research Institute, La Jolla, CA, and approved January 15, 2019 (received for review September 27, 2018) Ca2+ leak via ryanodine receptor type 2 (RyR2) can cause poten- heart diseases associated with both atrial and ventricular arrhyth- tially fatal arrhythmias in a variety of heart diseases and has also mia (9). Mutations in RyR2 and its binding partners, which increase + been implicated in neurodegenerative and seizure disorders, mak- SR Ca2 leak, cause primary atrial and ventricular arrhythmia ing RyR2 an attractive therapeutic target for drug development. syndromes such as catecholaminergic polymorphic ventricular Here we synthesized and investigated the fungal natural product tachycardia (CPVT), providing strong evidence for the mechanistic and known insect RyR antagonist (−)-verticilide and several conge- contribution of RyR2 to arrhythmia risk in humans (10). Further ners to determine their activity against mammalian RyR2. Although support comes from gene-targeted mouse models of CPVT, where + the cyclooligomeric depsipeptide natural product (−)-verticilide had catecholamine-induced spontaneous Ca2 release from the SR no effect, its nonnatural enantiomer [ent-(+)-verticilide] signifi- via RyR2 generates potentially fatal cardiac arrhythmias (11, 12).
    [Show full text]
  • Calcium-Induced Calcium Release in Smooth Muscle7 Loose Coupling
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central Calcium-induced Calcium Release in Smooth Muscle✪ Loose Coupling between the Action Potential and Calcium Release M.L. Collier, G. Ji, Y.-X. Wang, and M.I. Kotlikoff From the Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6046 abstract Calcium-induced calcium release (CICR) has been observed in cardiac myocytes as elementary cal- cium release events (calcium sparks) associated with the opening of L-type Ca2ϩ channels. In heart cells, a tight coupling between the gating of single L-type Ca2ϩ channels and ryanodine receptors (RYRs) underlies calcium re- lease. Here we demonstrate that L-type Ca2ϩ channels activate RYRs to produce CICR in smooth muscle cells in the form of Ca2ϩ sparks and propagated Ca2ϩ waves. However, unlike CICR in cardiac muscle, RYR channel open- ing is not tightly linked to the gating of L-type Ca2ϩ channels. L-type Ca2ϩ channels can open without triggering Ca2ϩ sparks and triggered Ca2ϩ sparks are often observed after channel closure. CICR is a function of the net flux of Ca2ϩ ions into the cytosol, rather than the single channel amplitude of L-type Ca2ϩ channels. Moreover, unlike CICR in striated muscle, calcium release is completely eliminated by cytosolic calcium buffering. Thus, L-type Ca2ϩ channels are loosely coupled to RYR through an increase in global [Ca2ϩ] due to an increase in the effective distance between L-type Ca2ϩ channels and RYR, resulting in an uncoupling of the obligate relationship that exists in striated muscle between the action potential and calcium release.
    [Show full text]
  • Characterization of Cecal Smooth Muscle Contraction in Laying Hens
    veterinary sciences Communication Characterization of Cecal Smooth Muscle Contraction in Laying Hens Katrin Röhm 1, Martin Diener 2 , Korinna Huber 1 and Jana Seifert 1,* 1 Institute of Animal Science, University of Hohenheim, 70593 Stuttgart, Germany; [email protected] (K.R.); [email protected] (K.H.) 2 Institute of Veterinary Physiology and Biochemistry, Justus-Liebig University, 35392 Gießen, Germany; [email protected] * Correspondence: [email protected] Abstract: The ceca play an important role in the physiology of the gastrointestinal tract in chickens. Nevertheless, there is a gap of knowledge regarding the functionality of the ceca in poultry, especially with respect to physiological cecal smooth muscle contraction. The aim of the current study is the ex vivo characterization of cecal smooth muscle contraction in laying hens. Muscle strips of circular cecal smooth muscle from eleven hens are prepared to investigate their contraction ex vivo. Contraction is detected using an isometric force transducer, determining its frequency, height and intensity. Spontaneous contraction of the chicken cecal smooth muscle and the influence of buffers (calcium-free buffer and potassium-enriched buffer) and drugs (carbachol, nitroprusside, isoprenaline and Verapamil) affecting smooth muscle contraction at different levels are characterized. A decrease in smooth muscle contraction is observed when a calcium-free buffer is used. Carbachol causes an increase in smooth muscle contraction, whereas atropine inhibits contraction. Nitroprusside, isoprenaline and Verapamil result in a depression of smooth muscle contraction. In conclusion, the present results confirm a similar contraction behavior of cecal smooth muscles in laying hens as Citation: Röhm, K.; Diener, M.; shown previously in other species.
    [Show full text]
  • Microarchitecture of the Dyad
    Cardiovascular Research (2013) 98, 169–176 SPOTLIGHT REVIEW doi:10.1093/cvr/cvt025 Microarchitecture of the dyad David R.L. Scriven, Parisa Asghari, and Edwin D.W. Moore* Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3 Received 12 December 2012; revised 2 February 2013; accepted 4 February 2013; online publish-ahead-of-print 11 February 2013 Downloaded from https://academic.oup.com/cardiovascres/article/98/2/169/278625 by guest on 23 September 2021 Abstract This review highlights recent and ongoing discoveries that are transforming the previously held view of dyad structure and function. New data show that dyads vary greatly in both structure and in their associated molecules. Dyads can contain varying numbers of type 2 ryanodine receptor (RYR2) clusters that range in size from one to hundreds of tetramers and they can adopt numerous orientations other than the expected checkerboard. The association of Cav1.2 with RYR2, which defines the couplon, is not absolute, leading to a number of scenarios such as dyads without couplons and those in which only a fraction of the clusters are in couplons. Different dyads also vary in the transporters and exchangers with which they are associated producing functional differences that amplify their structural diversity. The essential role of proteins, such as junctophilin-2, calsequestrin, triadin, and junctin that main- tain both the functional and structural integrity of the dyad have recently been elucidated giving a new mechanistic understanding of heart diseases, such as arrhythmias, hypertension, failure, and sudden cardiac death.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Difference in Allelic Expression of the CLCN1 Gene and the Possible Influence on the Myotonia Congenita Phenotype
    European Journal of Human Genetics (2004) 12, 738–743 & 2004 Nature Publishing Group All rights reserved 1018-4813/04 $30.00 www.nature.com/ejhg ARTICLE Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype Morten Dun1*, Eskild Colding-Jrgensen2, Morten Grunnet3,5, Thomas Jespersen3, John Vissing4 and Marianne Schwartz1 1Department of Clinical Genetics, 4062, University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; 2Department of Clinical Neurophysiology 3063,University Hospital, Rigshospitalet, Blegdamsvej 9, DK- 2100 Copenhagen, Denmark; 3Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark; 4Department of Neurology and The Copenhagen Muscle Research Center, University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark Mutations in the CLCN1 gene, encoding a muscle-specific chloride channel, can cause either recessive or dominant myotonia congenita (MC). The recessive form, Becker’s myotonia, is believed to be caused by two loss-of-function mutations, whereas the dominant form, Thomsen’s myotonia, is assumed to be a consequence of a dominant-negative effect. However, a subset of CLCN1 mutations can cause both recessive and dominant MC. We have identified two recessive and two dominant MC families segregating the common R894X mutation. Real-time quantitative RT-PCR did not reveal any obvious association between the total CLCN1 mRNA level in muscle and the mode of inheritance, but the dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele. Variation in allelic expression has not previously been described for CLCN1, and our finding suggests that allelic variation may be an important modifier of disease progression in myotonia congenita.
    [Show full text]
  • Back-To-Basics: the Intricacies of Muscle Contraction
    Back-to- MIOTA Basics: The CONFERENCE OCTOBER 11, Intricacies 2019 CHERI RAMIREZ, MS, of Muscle OTRL Contraction OBJECTIVES: 1.Review the anatomical structure of a skeletal muscle. 2.Review and understand the process and relationship between skeletal muscle contraction with the vital components of the nervous system, endocrine system, and skeletal system. 3.Review the basic similarities and differences between skeletal muscle tissue, smooth muscle tissue, and cardiac muscle tissue. 4.Review the names, locations, origins, and insertions of the skeletal muscles found in the human body. 5.Apply the information learned to enhance clinical practice and understanding of the intricacies and complexity of the skeletal muscle system. 6.Apply the information learned to further educate clients on the importance of skeletal muscle movement, posture, and coordination in the process of rehabilitation, healing, and functional return. 1. Epithelial Four Basic Tissue Categories 2. Muscle 3. Nervous 4. Connective A. Loose Connective B. Bone C. Cartilage D. Blood Introduction There are 3 types of muscle tissue in the muscular system: . Skeletal muscle: Attached to bones of skeleton. Voluntary. Striated. Tubular shape. Cardiac muscle: Makes up most of the wall of the heart. Involuntary. Striated with intercalated discs. Branched shape. Smooth muscle: Found in walls of internal organs and walls of vascular system. Involuntary. Non-striated. Spindle shape. 4 Structure of a Skeletal Muscle Skeletal Muscles: Skeletal muscles are composed of: • Skeletal muscle tissue • Nervous tissue • Blood • Connective tissues 5 Connective Tissue Coverings Connective tissue coverings over skeletal muscles: .Fascia .Tendons .Aponeuroses 6 Fascia: Definition: Layers of dense connective tissue that separates muscle from adjacent muscles, by surrounding each muscle belly.
    [Show full text]
  • Muscle Physiology Dr
    Muscle Physiology Dr. Ebneshahidi Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Skeletal Muscle Figure 9.2 (a) Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Functions of the muscular system . 1. Locomotion . 2. Vasoconstriction and vasodilatation- constriction and dilation of blood vessel Walls are the results of smooth muscle contraction. 3. Peristalsis – wavelike motion along the digestive tract is produced by the Smooth muscle. 4. Cardiac motion . 5. Posture maintenance- contraction of skeletal muscles maintains body posture and muscle tone. 6. Heat generation – about 75% of ATP energy used in muscle contraction is released as heat. Copyright. © 2004 Pearson Education, Inc., publishing as Benjamin Cummings . Striation: only present in skeletal and cardiac muscles. Absent in smooth muscle. Nucleus: smooth and cardiac muscles are uninculcated (one nucleus per cell), skeletal muscle is multinucleated (several nuclei per cell ). Transverse tubule ( T tubule ): well developed in skeletal and cardiac muscles to transport calcium. Absent in smooth muscle. Intercalated disk: specialized intercellular junction that only occurs in cardiac muscle. Control: skeletal muscle is always under voluntary control‚ with some exceptions ( the tongue and pili arrector muscles in the dermis). smooth and cardiac muscles are under involuntary control. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Innervation: motor unit . a) a motor nerve and a myofibril from a neuromuscular junction where gap (called synapse) occurs between the two structures. at the end of motor nerve‚ neurotransmitter (i.e. acetylcholine) is stored in synaptic vesicles which will release the neurotransmitter using exocytosis upon the stimulation of a nerve impulse. Across the synapse the surface the of myofibril contains receptors that can bind with the neurotransmitter.
    [Show full text]
  • Calcium Signaling and Cardiac Arrhythmias
    Review Calcium Signaling Series Donald M. Bers, Guest Editor Calcium Signaling and Cardiac Arrhythmias Andrew P. Landstrom, Dobromir Dobrev, Xander H.T. Wehrens Abstract: There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular Downloaded from tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca2+-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca2+ in normal cardiac function—in particular, excitation–contraction coupling and normal electric rhythms. The functional involvement of Ca2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused 2+ http://circres.ahajournals.org/ by mutations in Ca -handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes. (Circ Res. 2017;120:1969-1993. DOI: 10.1161/CIRCRESAHA.117.310083.) Key Words: arrhythmias, cardiac ■ atrial fibrillation ■ calcium channels ■ cardiomyopathy ■ ryanodine receptor calcium release channel 2+ by guest on June 11, 2017 he bivalent cation calcium (Ca ) represents one of the Overview of Excitation–Contraction Tmost ubiquitous signal transduction molecules known.1 Coupling in the Heart It mediates a diverse array of biological functions including Regular contraction of the heart requires the conversion of muscle contraction, cellular exocytosis, neuronal activity, and electric activation (excitation) into mechanical force (con- triggering of programmed cell death.
    [Show full text]
  • Comprehensive Exonic Sequencing of Known Ataxia Genes in Episodic Ataxia
    biomedicines Article Comprehensive Exonic Sequencing of Known Ataxia Genes in Episodic Ataxia Neven Maksemous, Heidi G. Sutherland, Robert A. Smith, Larisa M. Haupt and Lyn R. Griffiths * Genomics Research Centre, Institute of Health and Biomedical Innovation (IHBI), School of Biomedical Sciences, Queensland University of Technology (QUT), Q Block, 60 Musk Ave, Kelvin Grove Campus, Brisbane, Queensland 4059, Australia; [email protected] (N.M.); [email protected] (H.G.S.); [email protected] (R.A.S.); [email protected] (L.M.H.) * Correspondence: lyn.griffi[email protected]; Tel.: +61-7-3138-6100 Received: 4 May 2020; Accepted: 21 May 2020; Published: 25 May 2020 Abstract: Episodic Ataxias (EAs) are a small group (EA1–EA8) of complex neurological conditions that manifest as incidents of poor balance and coordination. Diagnostic testing cannot always find causative variants for the phenotype, however, and this along with the recently proposed EA type 9 (EA9), suggest that more EA genes are yet to be discovered. We previously identified disease-causing mutations in the CACNA1A gene in 48% (n = 15) of 31 patients with a suspected clinical diagnosis of EA2, and referred to our laboratory for CACNA1A gene testing, leaving 52% of these cases (n = 16) with no molecular diagnosis. In this study, whole exome sequencing (WES) was performed on 16 patients who tested negative for CACNA1A mutations. Tiered analysis of WES data was performed to first explore (Tier-1) the ataxia and ataxia-associated genes (n = 170) available in the literature and databases for comprehensive EA molecular genetic testing; we then investigated 353 ion channel genes (Tier-2).
    [Show full text]
  • Ryanodine Receptor Cluster Size Sets the Tone in Cerebral Smooth Muscle
    COMMENTARY Ryanodine receptor cluster size sets the tone in cerebral smooth muscle COMMENTARY Christian Soellera,1 + Ryanodine receptors (RyRs) are large intracellular Ca2 WT mdx channels that provide the molecular basis of the pro- K+ K+ higher BK + + + cess termed Ca2 -induced Ca2 release (1). Ca2 sig- activity naling through RyRs has been shown to be critical for CaC BK BK skeletal, cardiac, and smooth muscle physiology (2) as well as for neurons (3) and secretory cells like pancre- larger RyR atic beta cells. RyRs were first seen in the electron RyRs RyRs clusters microscope as ∼30-nm-size particles (4), and it had SMCs been known from EM studies that they form clusters, SR SR typically in the narrow “junctional” space between sar- colemma and sarcoplasmic reticulum (SR) membranes. + Due to the inherent positive feedback of Ca2 -induced + Ca2 release, the size and shape of RyR clusters are expected to affect their functional activity. Indeed, de- SMCs SMCs tailed mathematical modeling suggests that RyR cluster- cerebral artery ing is important for determining the excitability of RyR- + mediated Ca2 release (5, 6) and could, in principle, also + affect the amount of Ca2 released in microscopic re- 2+ lease events termed Ca sparks (7). The experimental myogenic tone study of RyR clustering has received a boost with the reduced advent of optical superresolution microscopy, which myogenic has made the assessment of RyR cluster size more acces- sible by using essentially standard immunolabeling pro- tone tocols. When first applied in cardiac muscle cells, this myogenic tone (%) tone myogenic approach revealed a broad, approximately exponential vessel pressure (%) tone myogenic vessel pressure RyR cluster size distribution (8), which had previously not Fig.
    [Show full text]