scholarly journals Calcium Dependent Inactivation of CaV1.1 Channels in Adult Skeletal Muscle: A Possible Role of RyR1 Channels

2012 ◽  
Vol 102 (3) ◽  
pp. 125a ◽  
Author(s):  
Erick O. Hernández-Ochoa ◽  
Martin F. Schneider
Keyword(s):  
Skeletal Muscle ◽  
Adult Skeletal Muscle ◽  
Calcium Dependent ◽  
Dependent Inactivation

scholarly journals A CACNA1A variant associated with trigeminal neuralgia alters the gating of Cav2.1 channels

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Eder Gambeta ◽  
Maria A. Gandini ◽  
Ivana A. Souza ◽  
Laurent Ferron ◽  
Gerald W. Zamponi
Keyword(s):  
Trigeminal Neuralgia ◽  
Missense Mutation ◽  
Neurotransmitter Release ◽  
Trigeminal System ◽  
Wild Type ◽  
Calcium Dependent ◽  
Whole Cell Patch Clamp ◽  
C Terminus ◽  
Dependent Inactivation

AbstractA novel missense mutation in the CACNA1A gene that encodes the pore forming α1 subunit of the CaV2.1 voltage-gated calcium channel was identified in a patient with trigeminal neuralgia. This mutation leads to a substitution of proline 2455 by histidine (P2455H) in the distal C-terminus region of the channel. Due to the well characterized role of this channel in neurotransmitter release, our aim was to characterize the biophysical properties of the P2455H variant in heterologously expressed CaV2.1 channels. Whole-cell patch clamp recordings of wild type and mutant CaV2.1 channels expressed in tsA-201 cells reveal that the mutation mediates a depolarizing shift in the voltage-dependence of activation and inactivation. Moreover, the P2455H mutant strongly reduced calcium-dependent inactivation of the channel that is consistent with an overall gain of function. Hence, the P2455H CaV2.1 missense mutation alters the gating properties of the channel, suggesting that associated changes in CaV2.1-dependent synaptic communication in the trigeminal system may contribute to the development of trigeminal neuralgia.

scholarly journals FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis

2021 ◽  
Vol 118 (37) ◽  
pp. e2021013118 ◽  
Author(s):  
Sebastian Mathes ◽  
Alexandra Fahrner ◽  
Umesh Ghoshdastider ◽  
Hannes A. Rüdiger ◽  
Michael Leunig ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcriptional Activation ◽  
Human Skeletal Muscle ◽  
Muscle Growth ◽  
Muscle Cells ◽  
Adeno Associated Virus ◽  
Adult Skeletal Muscle

Aged skeletal muscle is markedly affected by fatty muscle infiltration, and strategies to reduce the occurrence of intramuscular adipocytes are urgently needed. Here, we show that fibroblast growth factor-2 (FGF-2) not only stimulates muscle growth but also promotes intramuscular adipogenesis. Using multiple screening assays upstream and downstream of microRNA (miR)-29a signaling, we located the secreted protein and adipogenic inhibitor SPARC to an FGF-2 signaling pathway that is conserved between skeletal muscle cells from mice and humans and that is activated in skeletal muscle of aged mice and humans. FGF-2 induces the miR-29a/SPARC axis through transcriptional activation of FRA-1, which binds and activates an evolutionary conserved AP-1 site element proximal in the miR-29a promoter. Genetic deletions in muscle cells and adeno-associated virus–mediated overexpression of FGF-2 or SPARC in mouse skeletal muscle revealed that this axis regulates differentiation of fibro/adipogenic progenitors in vitro and intramuscular adipose tissue (IMAT) formation in vivo. Skeletal muscle from human donors aged >75 y versus <55 y showed activation of FGF-2–dependent signaling and increased IMAT. Thus, our data highlights a disparate role of FGF-2 in adult skeletal muscle and reveals a pathway to combat fat accumulation in aged human skeletal muscle.

scholarly journals Role of synemin, an intermediate filament protein, in adult skeletal muscle (1102.25)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Karla Garcia‐Pelagio ◽  
Joaquin Muriel ◽  
Linda Lund ◽  
Meredith Bond ◽  
Robert Bloch
Keyword(s):  
Skeletal Muscle ◽  
Intermediate Filament ◽  
Intermediate Filament Protein ◽  
Adult Skeletal Muscle ◽  
Filament Protein

scholarly journals Calcineurin Activity Is Required for the Initiation of Skeletal Muscle Differentiation

2000 ◽  
Vol 149 (3) ◽  
pp. 657-666 ◽  
Author(s):  
Bret B. Friday ◽  
Valerie Horsley ◽  
Grace K. Pavlath
Keyword(s):  
Skeletal Muscle ◽  
Cell Fusion ◽  
Transcriptional Activation ◽  
Active Form ◽  
Extracellular Calcium ◽  
Molecular Signaling ◽  
Phenotypic Differentiation ◽  
Calcium Dependent ◽  
Sequence Of Events

Differentiation of skeletal muscle myoblasts follows an ordered sequence of events: commitment, cell cycle withdrawal, phenotypic differentiation, and finally cell fusion to form multinucleated myotubes. The molecular signaling pathways that regulate the progression are not well understood. Here we investigate the potential role of calcium and the calcium-dependent phosphatase calcineurin in myogenesis. Commitment, phenotypic differentiation, and cell fusion are identified as distinct calcium-regulated steps, based on the extracellular calcium concentration required for the expression of morphological and biochemical markers specific to each of these stages. Furthermore, differentiation is inhibited at the commitment stage by either treatment with the calcineurin inhibitor cyclosporine A (CSA) or expression of CAIN, a physiological inhibitor of calcineurin. Retroviral-mediated gene transfer of a constitutively active form of calcineurin is able to induce myogenesis only in the presence of extracellular calcium, suggesting that multiple calcium-dependent pathways are required for differentiation. The mechanism by which calcineurin initiates differentiation includes transcriptional activation of myogenin, but does not require the participation of NFAT. We conclude that commitment of skeletal muscle cells to differentiation is calcium and calcineurin-dependent, but NFAT-independent.

scholarly journals Calcium-dependent inactivation controls cardiac L-type Ca2+ currents under β-adrenergic stimulation

2019 ◽  
Vol 151 (6) ◽  
pp. 786-797 ◽  
Author(s):  
Danna Morales ◽  
Tamara Hermosilla ◽  
Diego Varela
Keyword(s):  
Calcium Current ◽  
Calcium Currents ◽  
Adrenergic Stimulation ◽  
Sodium Calcium Exchanger ◽  
Adrenergic Agonist ◽  
Rat Cardiomyocytes ◽  
Calcium Dependent ◽  
Sodium Calcium ◽  
Dependent Inactivation

The activity of L-type calcium channels is associated with the duration of the plateau phase of the cardiac action potential (AP) and it is controlled by voltage- and calcium-dependent inactivation (VDI and CDI, respectively). During β-adrenergic stimulation, an increase in the L-type current and parallel changes in VDI and CDI are observed during square pulses stimulation; however, how these modifications impact calcium currents during an AP remains controversial. Here, we examined the role of both inactivation processes on the L-type calcium current activity in newborn rat cardiomyocytes in control conditions and after stimulation with the β-adrenergic agonist isoproterenol. Our approach combines a self-AP clamp (sAP-Clamp) with the independent inhibition of VDI or CDI (by overexpressing CaVβ2a or calmodulin mutants, respectively) to directly record the L-type calcium current during the cardiac AP. We find that at room temperature (20–23°C) and in the absence of β-adrenergic stimulation, the L-type current recapitulates the AP kinetics. Furthermore, under our experimental setting, the activity of the sodium–calcium exchanger (NCX) does not affect the shape of the AP. We find that hindering either VDI or CDI prolongs the L-type current and the AP in parallel, suggesting that both inactivation processes modulate the L-type current during the AP. In the presence of isoproterenol, wild-type and VDI-inhibited cardiomyocytes display mismatched L-type calcium current with respect to their AP. In contrast, CDI-impaired cells maintain L-type current with kinetics similar to its AP, demonstrating that calcium-dependent inactivation governs L-type current kinetics during β-adrenergic stimulation.

Alpha 7 beta 1 integrin is a component of the myotendinous junction on skeletal muscle

1993 ◽  
Vol 106 (2) ◽  
pp. 579-589 ◽  
Author(s):  
Z.Z. Bao ◽  
M. Lakonishok ◽  
S. Kaufman ◽  
A.F. Horwitz
Keyword(s):  
Skeletal Muscle ◽  
Cytoplasmic Domain ◽  
Cross Reactivity ◽  
Myotendinous Junction ◽  
Integrin Subunit ◽  
Adult Skeletal Muscle ◽  
Beta 1 Integrin ◽  
Alpha 7 ◽  
Adhesion Plaque

Immunization against a 70 kDa band that co-purifies with skeletal muscle integrins has resulted in an antibody directed against the avain alpha 7 integrin subunit. The specificity of the antibody was established by patterns of tissue staining and cross-reactivity with antibodies directed against the cytoplasmic domain of the rat alpha 7 cytoplasmic domain. On sections of adult skeletal muscle the alpha 7 integrin was enriched in the myotendinous junction (MTJ). This localization was unique as neither the alpha 1, alpha 3, alpha 5, alpha 6 and alpha v subunit localizes in the myotendinous junction. The distribution of the alpha 7 subunit in the MTJ was examined during embryonic development. alpha 7 expression in the junction is first apparent around embryo day 14 and is almost exclusively at the developing MTJ at this stage. alpha 3 is expressed with distinctive punctate staining around the junctional area in earlier embryos (11-day). The time of appearance of the alpha 7 subunit in the MTJ correlates with the insertion of myofibrils into subsarcolemmal densities and folding of the junctional membrane, suggesting a role of the alpha 7 integrin in this process. Vinculin is present throughout development of the myotendinous junction, suggesting that the alpha 7 integrin recognizes a preformed cytoskeletal structure. The presence of the alpha 7 subunit in the myotendinous junction and the alpha 5 subunit in the adhesion plaque demonstrates a molecular difference between these two adherens junctions. It also points to possible origins of junctional specificity on muscle. Differences between these two junctions were developed further using an antibody against phosphotyrosine (PY20). Phosphotyrosine is thought to participate in the organization and stabilization of adhesions. The focal adhesion and the neuromuscular junction, but not the MTJ, contained proteins phosphorylated on tyrosine.

scholarly journals Submaximal Responses in Calcium-triggered Exocytosis Are Explained by Differences in the Calcium Sensitivity of Individual Secretory Vesicles

1998 ◽  
Vol 112 (5) ◽  
pp. 559-567 ◽  
Author(s):  
Paul S. Blank ◽  
Myoung-Soon Cho ◽  
Steven S. Vogel ◽  
Doron Kaplan ◽  
Albert Kang ◽  
...  
Keyword(s):  
Calcium Sensitivity ◽  
Secretory Vesicle ◽  
Secretory Vesicles ◽  
Calcium Dependent ◽  
Sea Urchin Egg ◽  
Dependent Inactivation ◽  
Graded Response ◽  
Vesicle Exocytosis

A graded response to calcium is the defining feature of calcium-regulated exocytosis. That is, there exist calcium concentrations that elicit submaximal exocytotic responses in which only a fraction of the available population of secretory vesicles fuse. The role of calcium-dependent inactivation in defining the calcium sensitivity of sea urchin egg secretory vesicle exocytosis in vitro was examined. The cessation of fusion in the continued presence of calcium was not due to calcium-dependent inactivation. Rather, the calcium sensitivity of individual vesicles within a population of exocytotic vesicles is heterogeneous. Any specific calcium concentration above threshold triggered subpopulations of vesicles to fuse and the size of the subpopulations was dependent upon the magnitude of the calcium stimulus. The existence of multiple, stable subpopulations of vesicles is consistent with a fusion process that requires the action of an even greater number of calcium ions than the numbers suggested by models based on the assumption of a homogeneous vesicle population.

scholarly journals Brain-derived Neurotrophic Factor Regulates Satellite Cell Differentiation and Skeltal Muscle Regeneration

2010 ◽  
Vol 21 (13) ◽  
pp. 2182-2190 ◽  
Author(s):  
Charlene Clow ◽  
Bernard J. Jasmin
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Neurotrophic Factor ◽  
Cell Function ◽  
Brain Derived Neurotrophic Factor ◽  
Postnatal Growth ◽  
Adult Skeletal Muscle

In adult skeletal muscle, brain-derived neurotrophic factor (BDNF) is expressed in myogenic progenitors known as satellite cells. To functionally address the role of BDNF in muscle satellite cells and regeneration in vivo, we generated a mouse in which BDNF is specifically depleted from skeletal muscle cells. For comparative purposes, and to determine the specific role of muscle-derived BDNF, we also examined muscles of the complete BDNF−/− mouse. In both models, expression of the satellite cell marker Pax7 was significantly decreased. Furthermore, proliferation and differentiation of primary myoblasts was abnormal, exhibiting delayed induction of several markers of differentiation as well as decreased myotube size. Treatment with exogenous BDNF protein was sufficient to rescue normal gene expression and myotube size. Because satellite cells are responsible for postnatal growth and repair of skeletal muscle, we next examined whether regenerative capacity was compromised. After injury, BDNF-depleted muscle showed delayed expression of several molecular markers of regeneration, as well as delayed appearance of newly regenerated fibers. Recovery of wild-type BDNF levels was sufficient to restore normal regeneration. Together, these findings suggest that BDNF plays an important role in regulating satellite cell function and regeneration in vivo, particularly during early stages.

scholarly journals STAC proteins associate to the IQ domain of CaV1.2 and inhibit calcium-dependent inactivation

2018 ◽  
Vol 115 (6) ◽  
pp. 1376-1381 ◽  
Author(s):  
Marta Campiglio ◽  
Pierre Costé de Bagneaux ◽  
Nadine J. Ortner ◽  
Petronel Tuluc ◽  
Filip Van Petegem ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Calcium Channel ◽  
Muscle Disease ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Calcium Dependent ◽  
C Terminus ◽  
Dependent Inactivation ◽  
C1 Domain

The adaptor proteins STAC1, STAC2, and STAC3 represent a newly identified family of regulators of voltage-gated calcium channel (CaV) trafficking and function. The skeletal muscle isoform STAC3 is essential for excitation–contraction coupling and its mutation causes severe muscle disease. Recently, two distinct molecular domains in STAC3 were identified, necessary for its functional interaction with CaV1.1: the C1 domain, which recruits STAC proteins to the calcium channel complex in skeletal muscle triads, and the SH3-1 domain, involved in excitation–contraction coupling. These interaction sites are conserved in the three STAC proteins. However, the molecular domain in CaV1 channels interacting with the STAC C1 domain and the possible role of this interaction in neuronal CaV1 channels remained unknown. Using CaV1.2/2.1 chimeras expressed in dysgenic (CaV1.1−/−) myotubes, we identified the amino acids 1,641–1,668 in the C terminus of CaV1.2 as necessary for association of STAC proteins. This sequence contains the IQ domain and alanine mutagenesis revealed that the amino acids important for STAC association overlap with those making contacts with the C-lobe of calcium-calmodulin (Ca/CaM) and mediating calcium-dependent inactivation of CaV1.2. Indeed, patch-clamp analysis demonstrated that coexpression of either one of the three STAC proteins with CaV1.2 opposed calcium-dependent inactivation, although to different degrees, and that substitution of the CaV1.2 IQ domain with that of CaV2.1, which does not interact with STAC, abolished this effect. These results suggest that STAC proteins associate with the CaV1.2 C terminus at the IQ domain and thus inhibit calcium-dependent feedback regulation of CaV1.2 currents.

scholarly journals Functional properties of cardiac L-type calcium channels transiently expressed in HEK293 cells. Roles of alpha 1 and beta subunits.

1995 ◽  
Vol 105 (2) ◽  
pp. 289-305 ◽  
Author(s):  
M T Pérez-García ◽  
T J Kamp ◽  
E Marbán
Keyword(s):  
Skeletal Muscle ◽  
Calcium Channel ◽  
Binding Sites ◽  
Beta Subunit ◽  
Hek293 Cells ◽  
Beta Subunits ◽  
Calcium Dependent ◽  
Dependent Inactivation ◽  
Kinetics Of ◽  
Macroscopic Kinetics

The cardiac dihydropyridine-sensitive calcium channel was transiently expressed in HEK293 cells by transfecting the rabbit cardiac calcium channel alpha 1 subunit (alpha 1C) alone or in combination with the rabbit calcium channel beta subunit cloned from skeletal muscle. Transfection with alpha 1C alone leads to the expression of inward, voltage-activated, calcium or barium currents that exhibit dihydropyridine sensitivity and voltage- as well as calcium-dependent inactivation. Coexpression of the skeletal muscle beta subunit increases current density and the number of high-affinity dihydropyridine binding sites and also affects the macroscopic kinetics of the current. Recombinant alpha 1C beta channels exhibit a slowing of activation and a faster inactivation rate when either calcium or barium carries the charge. Our data suggest that both an increase in the number of channels as well as modulatory effects on gating underlie the modifications observed upon beta subunit coexpression.

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