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Ca2+-dependent regulations and signaling in skeletal muscle: from electro-mechanical coupling to adaptation.

Gehlert S, Bloch W, Suhr F - Int J Mol Sci (2015)

Bottom Line: Calcium (Ca2+) plays a pivotal role in almost all cellular processes and ensures the functionality of an organism.In skeletal muscle fibers, Ca(2+) is critically involved in the innervation of skeletal muscle fibers that results in the exertion of an action potential along the muscle fiber membrane, the prerequisite for skeletal muscle contraction.Furthermore and among others, Ca(2+) regulates also intracellular processes, such as myosin-actin cross bridging, protein synthesis, protein degradation and fiber type shifting by the control of Ca(2+)-sensitive proteases and transcription factors, as well as mitochondrial adaptations, plasticity and respiration.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medcine, German Sport University Cologne, Am Sportpark Müngersdorf 6, Cologne 50933, Germany. Gehlert@dshs-koeln.de.

ABSTRACT
Calcium (Ca2+) plays a pivotal role in almost all cellular processes and ensures the functionality of an organism. In skeletal muscle fibers, Ca(2+) is critically involved in the innervation of skeletal muscle fibers that results in the exertion of an action potential along the muscle fiber membrane, the prerequisite for skeletal muscle contraction. Furthermore and among others, Ca(2+) regulates also intracellular processes, such as myosin-actin cross bridging, protein synthesis, protein degradation and fiber type shifting by the control of Ca(2+)-sensitive proteases and transcription factors, as well as mitochondrial adaptations, plasticity and respiration. These data highlight the overwhelming significance of Ca(2+) ions for the integrity of skeletal muscle tissue. In this review, we address the major functions of Ca(2+) ions in adult muscle but also highlight recent findings of critical Ca(2+)-dependent mechanisms essential for skeletal muscle-regulation and maintenance.

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Related in: MedlinePlus

RyR1 channels induce rapid and high gradients in Ca2+ ion concentration between luminal compartments of the SR and surrounding sarcoplasm of myofbrills. (A) RyR1 opening is primarily controlled by the voltage dependent activation of DHPR which mechanically interacts with RyR1 and regulates channel opening (voltage gating). Further and adjacent RyR1 channels are opened by voltage-independent RyR1-RyR1 interactions (coupled gating) which create locally high Ca2+ ion gradients. On the luminar side of the SR, RyR1 channel opening is supported by the combined mechanical interaction with triadin, junctin and the SR membrane. High Ca2+ ion concentrations in the SR further supports channel open probability. On the sarcoplasmic side and at low Ca2+ concentrations, high amounts of Ca2+ unbound apoCaM supports increased open probability and activity of RyR1 while Ca2+-activated CaM inhibits RyR1. PKA and CaMKII have binding sites on RyR1 subunits and are able to phosphorylate RyR1 and modulate channel activity; and (B) Upon elevation of sarcoplasmic Ca2+ levels due to RyR1 channel opening, decreased Ca2+ ion levels in SR inhibit RyR1 channel activity. Sarcoplasmic Ca2+ levels increase CaM levels which activate CaMKII, IV and calcineurin. CaM inhibits RyR1 channel activity on the sarcoplasmic side of RyR1 while CaMKII binds to and phosphorylates RyR1. Hyperphosphorylation of RyR1 via PKA and CaMKII may lead to increased dissociation of FKBP12, higher open probability of RyR1 channels and decreased contractility of skeletal muscle under resting conditions. Increased SERCA activity facilitates rapid reuptake of Ca2+ ions into the SR.
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ijms-16-01066-f002: RyR1 channels induce rapid and high gradients in Ca2+ ion concentration between luminal compartments of the SR and surrounding sarcoplasm of myofbrills. (A) RyR1 opening is primarily controlled by the voltage dependent activation of DHPR which mechanically interacts with RyR1 and regulates channel opening (voltage gating). Further and adjacent RyR1 channels are opened by voltage-independent RyR1-RyR1 interactions (coupled gating) which create locally high Ca2+ ion gradients. On the luminar side of the SR, RyR1 channel opening is supported by the combined mechanical interaction with triadin, junctin and the SR membrane. High Ca2+ ion concentrations in the SR further supports channel open probability. On the sarcoplasmic side and at low Ca2+ concentrations, high amounts of Ca2+ unbound apoCaM supports increased open probability and activity of RyR1 while Ca2+-activated CaM inhibits RyR1. PKA and CaMKII have binding sites on RyR1 subunits and are able to phosphorylate RyR1 and modulate channel activity; and (B) Upon elevation of sarcoplasmic Ca2+ levels due to RyR1 channel opening, decreased Ca2+ ion levels in SR inhibit RyR1 channel activity. Sarcoplasmic Ca2+ levels increase CaM levels which activate CaMKII, IV and calcineurin. CaM inhibits RyR1 channel activity on the sarcoplasmic side of RyR1 while CaMKII binds to and phosphorylates RyR1. Hyperphosphorylation of RyR1 via PKA and CaMKII may lead to increased dissociation of FKBP12, higher open probability of RyR1 channels and decreased contractility of skeletal muscle under resting conditions. Increased SERCA activity facilitates rapid reuptake of Ca2+ ions into the SR.

Mentions: Ca2+ ions themselves have a high capability in modulating RyR1 channel activity and, thus, offer an important role in the modulation of their own release via modulation of RyR1 [66]. Ca2+-dependent modulation of the RyR1 channel occurs in different ways. As a direct effect, Ca2+ binds either to the high affinity and activating A-site of RyR1, which increases channel activity or the inhibitory I-site which then decreases RyR1 channel conductance. RyR1 is primarily activated at low Ca2+ concentration (0.5 µM) and inhibited by elevated concentrations of Ca2+ (0.15 mM). Hence, RyR1-induced Ca2+ release is directly affected by Ca2+ ions via a positive and negative feedback regulation. By this, RyR1 channel conductance is regulated by two distinct Ca2+ binding sites on the cytoplasmic domain of the RyR1, controlling and sensing luminal Ca2+ flux into modulated RyR1 channel conductance. Typically, at low Ca2+ concentration, CaM is preferentially not activated (apoCaM), whereas elevated Ca2+ concentration binds to and activates calmodulin (Ca2+-CaM) [67,68]. ApoCaM binds to and activates RyR1, whereas CaM inhibits RyR1 channel conductance. Activated CaM can further activate calmodulin kinase II (CaMKII) which, when activated, phosphorylates RyR1 [9,55]. This can contribute to the discussed increase or decrease in skeletal muscle contractility, which has been observed in response to the phosphorylation of RyR1 channel subunits. Figure 2 illustrates the activity of RyR1 channels upon inhibition and activation by interaction with the most important regulators.


Ca2+-dependent regulations and signaling in skeletal muscle: from electro-mechanical coupling to adaptation.

Gehlert S, Bloch W, Suhr F - Int J Mol Sci (2015)

RyR1 channels induce rapid and high gradients in Ca2+ ion concentration between luminal compartments of the SR and surrounding sarcoplasm of myofbrills. (A) RyR1 opening is primarily controlled by the voltage dependent activation of DHPR which mechanically interacts with RyR1 and regulates channel opening (voltage gating). Further and adjacent RyR1 channels are opened by voltage-independent RyR1-RyR1 interactions (coupled gating) which create locally high Ca2+ ion gradients. On the luminar side of the SR, RyR1 channel opening is supported by the combined mechanical interaction with triadin, junctin and the SR membrane. High Ca2+ ion concentrations in the SR further supports channel open probability. On the sarcoplasmic side and at low Ca2+ concentrations, high amounts of Ca2+ unbound apoCaM supports increased open probability and activity of RyR1 while Ca2+-activated CaM inhibits RyR1. PKA and CaMKII have binding sites on RyR1 subunits and are able to phosphorylate RyR1 and modulate channel activity; and (B) Upon elevation of sarcoplasmic Ca2+ levels due to RyR1 channel opening, decreased Ca2+ ion levels in SR inhibit RyR1 channel activity. Sarcoplasmic Ca2+ levels increase CaM levels which activate CaMKII, IV and calcineurin. CaM inhibits RyR1 channel activity on the sarcoplasmic side of RyR1 while CaMKII binds to and phosphorylates RyR1. Hyperphosphorylation of RyR1 via PKA and CaMKII may lead to increased dissociation of FKBP12, higher open probability of RyR1 channels and decreased contractility of skeletal muscle under resting conditions. Increased SERCA activity facilitates rapid reuptake of Ca2+ ions into the SR.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307291&req=5

ijms-16-01066-f002: RyR1 channels induce rapid and high gradients in Ca2+ ion concentration between luminal compartments of the SR and surrounding sarcoplasm of myofbrills. (A) RyR1 opening is primarily controlled by the voltage dependent activation of DHPR which mechanically interacts with RyR1 and regulates channel opening (voltage gating). Further and adjacent RyR1 channels are opened by voltage-independent RyR1-RyR1 interactions (coupled gating) which create locally high Ca2+ ion gradients. On the luminar side of the SR, RyR1 channel opening is supported by the combined mechanical interaction with triadin, junctin and the SR membrane. High Ca2+ ion concentrations in the SR further supports channel open probability. On the sarcoplasmic side and at low Ca2+ concentrations, high amounts of Ca2+ unbound apoCaM supports increased open probability and activity of RyR1 while Ca2+-activated CaM inhibits RyR1. PKA and CaMKII have binding sites on RyR1 subunits and are able to phosphorylate RyR1 and modulate channel activity; and (B) Upon elevation of sarcoplasmic Ca2+ levels due to RyR1 channel opening, decreased Ca2+ ion levels in SR inhibit RyR1 channel activity. Sarcoplasmic Ca2+ levels increase CaM levels which activate CaMKII, IV and calcineurin. CaM inhibits RyR1 channel activity on the sarcoplasmic side of RyR1 while CaMKII binds to and phosphorylates RyR1. Hyperphosphorylation of RyR1 via PKA and CaMKII may lead to increased dissociation of FKBP12, higher open probability of RyR1 channels and decreased contractility of skeletal muscle under resting conditions. Increased SERCA activity facilitates rapid reuptake of Ca2+ ions into the SR.
Mentions: Ca2+ ions themselves have a high capability in modulating RyR1 channel activity and, thus, offer an important role in the modulation of their own release via modulation of RyR1 [66]. Ca2+-dependent modulation of the RyR1 channel occurs in different ways. As a direct effect, Ca2+ binds either to the high affinity and activating A-site of RyR1, which increases channel activity or the inhibitory I-site which then decreases RyR1 channel conductance. RyR1 is primarily activated at low Ca2+ concentration (0.5 µM) and inhibited by elevated concentrations of Ca2+ (0.15 mM). Hence, RyR1-induced Ca2+ release is directly affected by Ca2+ ions via a positive and negative feedback regulation. By this, RyR1 channel conductance is regulated by two distinct Ca2+ binding sites on the cytoplasmic domain of the RyR1, controlling and sensing luminal Ca2+ flux into modulated RyR1 channel conductance. Typically, at low Ca2+ concentration, CaM is preferentially not activated (apoCaM), whereas elevated Ca2+ concentration binds to and activates calmodulin (Ca2+-CaM) [67,68]. ApoCaM binds to and activates RyR1, whereas CaM inhibits RyR1 channel conductance. Activated CaM can further activate calmodulin kinase II (CaMKII) which, when activated, phosphorylates RyR1 [9,55]. This can contribute to the discussed increase or decrease in skeletal muscle contractility, which has been observed in response to the phosphorylation of RyR1 channel subunits. Figure 2 illustrates the activity of RyR1 channels upon inhibition and activation by interaction with the most important regulators.

Bottom Line: Calcium (Ca2+) plays a pivotal role in almost all cellular processes and ensures the functionality of an organism.In skeletal muscle fibers, Ca(2+) is critically involved in the innervation of skeletal muscle fibers that results in the exertion of an action potential along the muscle fiber membrane, the prerequisite for skeletal muscle contraction.Furthermore and among others, Ca(2+) regulates also intracellular processes, such as myosin-actin cross bridging, protein synthesis, protein degradation and fiber type shifting by the control of Ca(2+)-sensitive proteases and transcription factors, as well as mitochondrial adaptations, plasticity and respiration.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medcine, German Sport University Cologne, Am Sportpark Müngersdorf 6, Cologne 50933, Germany. Gehlert@dshs-koeln.de.

ABSTRACT
Calcium (Ca2+) plays a pivotal role in almost all cellular processes and ensures the functionality of an organism. In skeletal muscle fibers, Ca(2+) is critically involved in the innervation of skeletal muscle fibers that results in the exertion of an action potential along the muscle fiber membrane, the prerequisite for skeletal muscle contraction. Furthermore and among others, Ca(2+) regulates also intracellular processes, such as myosin-actin cross bridging, protein synthesis, protein degradation and fiber type shifting by the control of Ca(2+)-sensitive proteases and transcription factors, as well as mitochondrial adaptations, plasticity and respiration. These data highlight the overwhelming significance of Ca(2+) ions for the integrity of skeletal muscle tissue. In this review, we address the major functions of Ca(2+) ions in adult muscle but also highlight recent findings of critical Ca(2+)-dependent mechanisms essential for skeletal muscle-regulation and maintenance.

Show MeSH
Related in: MedlinePlus