Impaired calcium release during fatigue

2008 ◽  
Vol 104 (1) ◽  
pp. 296-305 ◽  
Author(s):  
D. G. Allen ◽  
G. D. Lamb ◽  
H. Westerblad
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Action Potential ◽  
Inorganic Phosphate ◽  
Calcium Release ◽  
Voltage Sensor ◽  
Functional Importance ◽  
Intracellular Atp ◽  
Channel Opening ◽  
Sensor Activation

Impaired calcium release from the sarcoplasmic reticulum (SR) has been identified as a contributor to fatigue in isolated skeletal muscle fibers. The functional importance of this phenomenon can be quantified by the use of agents, such as caffeine, which can increase SR Ca2+ release during fatigue. A number of possible mechanisms for impaired calcium release have been proposed. These include reduction in the amplitude of the action potential, potentially caused by extracellular K+ accumulation, which may reduce voltage sensor activation but is counteracted by a number of mechanisms in intact animals. Reduced effectiveness of SR Ca2+ channel opening is caused by the fall in intracellular ATP and the rise in Mg2+ concentrations that occur during fatigue. Reduced Ca2+ available for release within the SR can occur if inorganic phosphate enters the SR and precipitates with Ca2+. Further progress requires the development of methods that can identify impaired SR Ca2+ release in intact, blood-perfused muscles and that can distinguish between the various mechanisms proposed.

scholarly journals cAMP-dependent regulation of IKs single-channel kinetics

2017 ◽  
Vol 149 (8) ◽  
pp. 781-798 ◽  
Author(s):  
Emely Thompson ◽  
Jodene Eldstrom ◽  
Maartje Westhoff ◽  
Donald McAfee ◽  
Elise Balse ◽  
...  
Keyword(s):  
Action Potential ◽  
Single Channel ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Surface Expression ◽  
Voltage Sensor ◽  
Single Channels ◽  
Adrenergic Stimulation ◽  
Channel Opening ◽  
Sensor Activation

The delayed potassium rectifier current, IKs, is composed of KCNQ1 and KCNE1 subunits and plays an important role in cardiac action potential repolarization. During β-adrenergic stimulation, 3′-5′-cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) phosphorylates KCNQ1, producing an increase in IKs current and a shortening of the action potential. Here, using cell-attached macropatches and single-channel recordings, we investigate the microscopic mechanisms underlying the cAMP-dependent increase in IKs current. A membrane-permeable cAMP analog, 8-(4-chlorophenylthio)-cAMP (8-CPT-cAMP), causes a marked leftward shift of the conductance–voltage relation in macropatches, with or without an increase in current size. Single channels exhibit fewer silent sweeps, reduced first latency to opening (control, 1.61 ± 0.13 s; cAMP, 1.06 ± 0.11 s), and increased higher-subconductance-level occupancy in the presence of cAMP. The E160R/R237E and S209F KCNQ1 mutants, which show fixed and enhanced voltage sensor activation, respectively, largely abolish the effect of cAMP. The phosphomimetic KCNQ1 mutations, S27D and S27D/S92D, are much less and not at all responsive, respectively, to the effects of PKA phosphorylation (first latency of S27D + KCNE1 channels: control, 1.81 ± 0.1 s; 8-CPT-cAMP, 1.44 ± 0.1 s, P < 0.05; latency of S27D/S92D + KCNE1: control, 1.62 ± 0.1 s; cAMP, 1.43 ± 0.1 s, nonsignificant). Using total internal reflection fluorescence microscopy, we find no overall increase in surface expression of the channel during exposure to 8-CPT-cAMP. Our data suggest that the cAMP-dependent increase in IKs current is caused by an increase in the likelihood of channel opening, combined with faster openings and greater occupancy of higher subconductance levels, and is mediated by enhanced voltage sensor activation.

scholarly journals Modulation of the Frequency of Spontaneous Sarcoplasmic Reticulum Ca2+ Release Events (Ca2+ Sparks) by Myoplasmic [Mg2+] in Frog Skeletal Muscle

1998 ◽  
Vol 111 (2) ◽  
pp. 207-224 ◽  
Author(s):  
Alain Lacampagne ◽  
Michael G. Klein ◽  
Martin F. Schneider
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Frog Skeletal Muscle ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Event Frequency ◽  
Open Time ◽  
Channel Opening ◽  
Sr Calcium Release

The modulation by internal free [Mg2+] of spontaneous calcium release events (Ca2+ “sparks”) from the sarcoplasmic reticulum (SR) was studied in depolarized notched frog skeletal muscle fibers using a laser scanning confocal microscope in line-scan mode (x vs. t). Over the range of [Mg2+] from 0.13 to 1.86 mM, decreasing the [Mg2+] induced an increase in the frequency of calcium release events in proportion to [Mg2+]−1.6. The change of event frequency was not due to changes in [Mg-ATP] or [ATP]. Analysis of individual SR calcium release event properties showed that the variation in event frequency induced by the change of [Mg2+] was not accompanied by any changes in the spatiotemporal spread (i.e., spatial half width or temporal half duration) of Ca2+ sparks. The increase in event frequency also had no effect on the distribution of event amplitudes. Finally, the rise time of calcium sparks was independent of the [Mg2+], indicating that the open time of the SR channel or channels underlying spontaneous calcium release events was not altered by [Mg2+] over the range tested. These results suggest that in resting skeletal fibers, [Mg2+] modulates the SR calcium release channel opening frequency by modifying the average closed time of the channel without altering the open time. A kinetic reaction scheme consistent with our results and those of bilayer and SR vesicle experiments indicates that physiological levels of resting Mg2+ may inhibit channel opening by occupying the site for calcium activation of the SR calcium release channel.

The Anatomy of the Sarcoplasmic Reticulum in Vertebrate Skeletal Muscle: Its Implications for Excitation Contraction Coupling

1982 ◽  
Vol 37 (7-8) ◽  
pp. 665-678 ◽  
Author(s):  
Joachim R. Sommer
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Action Potential ◽  
Cardiac Muscle ◽  
Calcium Release ◽  
Striated Muscle ◽  
Band Region ◽  
Terminal Cisterna ◽  
Transmitter Substance ◽  
Main Components

Abstract The sarcoplasmic reticulum in situ is an intricate tubular network that surrounds the contractile material in striated muscle cells. Its topographical relationship to other intracellular components, especially the myofibrils, is rather rigidly mainiained by a cytoskeleton which enmeshes Z line material and sarcoplasmic reticulum and, ultimately, is anchored at the plasmalemma. As a result, the two main components of the sarcoplasmic reticulum, the junctional SR and the free SR, retain their typical location in the A band region and in the I band region, respectively. The junc­tional SR, which is thought to be the site for calcium storage and release for contraction, is, thus, always well within one micron of the regulatory proteins associated with the actin filaments. The junctional SR, a synonym for terminal cisterna applying to both skeletal and cardiac muscle, is generally held to be involved in the translation of the action potential into calcium release, mainly because of the close topographic apposition between the junctional SR and the plasmalemma, especially in skeletal muscle. This attractive structure-function correlation is challenged by the observation that in bird cardiac muscle 80% of the junctional SR is spacially far removed from plas­malemma, the site of electrical activity. This anomalous topography is not in conflict with the notion that translation of the action potential into calcium release may be accomplished by a dif­fusible transmitter substance, e.g. calcium. Any hypothesis dealing with this problem must ac­ count for the anatomy of the bird heart.

scholarly journals Contractions of dysgenic skeletal muscle triggered by a potentiated, endogenous calcium current.

1991 ◽  
Vol 97 (4) ◽  
pp. 687-696 ◽  
Author(s):  
B A Adams ◽  
K G Beam
Keyword(s):  
Skeletal Muscle ◽  
Electrical Stimulation ◽  
Sarcoplasmic Reticulum ◽  
Calcium Current ◽  
Calcium Release ◽  
Voltage Sensor ◽  
Bay K 8644 ◽  
Direct Electrical Stimulation ◽  
External Calcium ◽  
Muscular Dysgenesis

The dihydropyridine (DHP) receptor of normal skeletal muscle is hypothesized to function as the voltage sensor for excitation-contraction (E-C) coupling, and also as the calcium channel underlying a slowly activating, DHP-sensitive current (termed ICa-s). Skeletal muscle from mice with muscular dysgenesis lacks both E-C coupling and ICa-s. However, dysgenic skeletal muscle does express a small DHP-sensitive calcium current (termed ICa-dvs) which is kinetically and pharmacologically distinct from ICa-s. We have examined the ability of ICa-dys, or the DHP receptor underlying it, to couple depolarization and contraction. Under most conditions ICa-dys is small (approximately 1 pA/pF) and dysgenic myotubes do not contract in response to sarcolemmal depolarization. However, in the combined presence of the DHP agonist Bay K 8644 (1 microM) and elevated external calcium (10 mM), ICa-dys is strongly potentiated and some dysgenic myotubes contract in response to direct electrical stimulation. These contractions are blocked by removing external calcium, by adding 0.5 mM cadmium to the bath, or by replacing Bay K 8644 with the DHP antagonist (+)-PN 200-110. Only myotubes having a density of ICa-dys greater than approximately 4 pA/pF produce detectible contractions, and the strength of contraction is positively correlated with the density of ICa-dys. Thus, unlike the contractions of normal myotubes, the contractions of dysgenic myotubes require calcium entry. These results demonstrate that the DHP receptor underlying ICa-dys is unable to function as a "voltage sensor" that directly couples membrane depolarization to calcium release from the sarcoplasmic reticulum.

scholarly journals Voltage sensor movements of CaV1.1 during an action potential in skeletal muscle fibers

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Quinton Banks ◽  
Hugo Bibollet ◽  
Minerva Contreras ◽  
Daniel F. Bennett ◽  
Roger A. Bannister ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Action Potential ◽  
Conformational Changes ◽  
Calcium Release ◽  
Muscle Fibers ◽  
Temporal Correlation ◽  
Voltage Sensor ◽  
Charge Movement ◽  
Voltage Gated ◽  
Extracellular Region

In excitation–contraction coupling (ECC), when the skeletal muscle action potential (AP) propagates into the transverse tubules, it modifies the conformational state of the voltage-gated calcium channels (CaV1.1). CaV1.1 serves as the voltage sensor for activation of calcium release from the sarcoplasmic reticulum (SR); however, many questions about this function persist. CaV1.1 α1 subunits contain four distinct homologous domains (I–IV). Each repeat includes six transmembranal helical segments; the voltage-sensing domain (VSD) is formed by S1–S4 segments, and the pore domain is formed by helices S5–S6. Because, in other voltage-gated channels, individual VSDs appear to be differentially involved in specific aspects of channel gating, here we thus hypothesized that not all the VSDs in CaV1.1 contribute equally to calcium-release activation. Yet, the voltage-sensor movements during an AP (the physiological stimulus for the muscle fiber) have not been previously measured in muscle. Reorientation of VSDs I–IV in CaV1.1 during an AP should generate a small but measurable electrical current. Still, neither the voltage-sensor charge movement during the AP nor the contribution of the individual VSDs to voltage-gated calcium release have been previously monitored. Here, we electrically monitor VSD movements using an AP voltage-clamp technique applied to muscle fibers. We introduce AP-fluorometry, a variant of the functional site-directed fluorescence, to track the movement of each VSD via a cysteine substitution on the extracellular region of S4 of each VSD and its labeling with a cysteine-reacting fluorescent probe, which served as an optical reporter of local rearrangements. Independent optical recordings of AP and calcium transients were performed to establish the temporal correlation between AP, AP-elicited charge movement, VSDs conformational changes, and calcium release flux. Our results support the hypothesis that not all VSDs in CaV1.1 contribute to ECC.

Caffeine treatment inhibits drug-induced calcium release from sarcoplasmic reticulum and caffeine contracture but not tetanus in frog skeletal muscle

1989 ◽  
Vol 67 (8) ◽  
pp. 890-895 ◽  
Author(s):  
Makoto Koshita ◽  
Toshiharu Oba
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Electrical Stimulus ◽  
Final Concentration ◽  
Heavy Fraction ◽  
Frog Skeletal Muscle ◽  
Drug Induced ◽  
Physiological Signal ◽  
Caffeine Contracture

Effects of pretreatment with caffeine on Ca2+ release induced by caffeine, thymol, quercetin, or p-chloromercuriphenylsulfonic acid (pCMPS) from the heavy fraction of sarcoplasmic reticulum (SR) were studied and compared with those effects on caffeine contracture and tetanus tension in single fibers of frog skeletal muscle. Caffeine (1–5 mM) did induce transient Ca2+ release from SR vesicles, but subsequent further addition of caffeine (10 mM, final concentration) induced little Ca2+ release. Ca2+ release induced by thymol, quercetin, or pCMPS was also inhibited by pretreatment with caffeine. In single muscle fibers, pretreatment with caffeine (1–5 mM) partially reduced the contracture induced by 10 mM caffeine. However, tetanus tension was almost maximally induced by electrical stimulus in caffeine-treated fibers. These results indicate that SR, which becomes less sensitive to caffeine, thymol, quercetin, or pCMPS by pretreatment with caffeine, can still respond to a physiological signal transmitted from transverse tubules.Key words: Ca2+ release, sarcoplasmic reticulum, caffeine, tetanus, skeletal muscle.

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