The voltage sensor of excitation–contraction coupling in mammals: Inactivation and interaction with Ca2+

Ferreira, Juan J.; Pequera, Germán; Manno, Carlo; Rı́os, Eduardo; Brum, Gustavo

doi:10.1085/jgp.201611725

Cited by 12 publications

(9 citation statements)

References 71 publications

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“…The ΔF/F was half maximal at an AP peak of –21.0 ± 4.0 mV with a slope factor of 5.9 ± 1.7 mV. This relationship between peak voltage and Ca 2+ transient was within the range of values obtained from voltage-clamp studies of mouse muscle fibers ( Wang et al, 1999 ; Ferreira Gregorio et al, 2017 ). These data suggest that APs peaking below –30 mV trigger little to no elevation of intracellular Ca 2+ and hence generate little to no force.…”

Section: Resultssupporting

confidence: 73%

“…When severe enough, depolarization of the resting membrane potential triggers both inactivation of Nav1.4 channels and inactivation of Ca 2+ release from the SR ( Ferreira Gregorio et al, 2017 ; Cannon, 2018 ; Hernández-Ochoa and Schneider, 2018 ). The trigger for Ca 2+ release from the SR is gating charge movement of Cav1.1 channels, which has a midpoint of inactivation of –57 mV ( Ferreira Gregorio et al, 2017 ); a membrane potential at which ΔF/F sharply decreases.…”

Section: Resultsmentioning

confidence: 99%

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The role of action potential changes in depolarization-induced failure of excitation contraction coupling in mouse skeletal muscle

Wang

Nawaz

Dupont

et al. 2022

eLife

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Excitation-contraction coupling (ECC) is the process by which electrical excitation of muscle is converted into force generation. Depolarization of skeletal muscle resting potential contributes to failure of ECC in diseases such as periodic paralysis, intensive care unit acquired weakness and possibly fatigue of muscle during vigorous exercise. When extracellular K+ is raised to depolarize the resting potential, failure of ECC occurs suddenly, over a narrow range of resting potentials. Simultaneous imaging of Ca2+ transients and recording of action potentials (APs) demonstrated failure to generate Ca2+ transients when APs peaked at potentials more negative than –30mV. An AP property that closely correlated with failure of the Ca2+ transient was the integral of AP voltage with respect to time. Simultaneous recording of Ca2+ transients and APs with electrodes separated by 1.6mm revealed AP conduction fails when APs peak below –21mV. We hypothesize propagation of APs and generation of Ca2+ transients are governed by distinct AP properties: AP conduction is governed by AP peak, whereas Ca2+ release from the sarcoplasmic reticulum is governed by AP integral. The reason distinct AP properties may govern distinct steps of ECC is the kinetics of the ion channels involved. Na channels, which govern propagation, have rapid kinetics and are insensitive to AP width (and thus AP integral) whereas Ca2+ release is governed by gating charge movement of Cav1.1 channels, which have slower kinetics such that Ca2+ release is sensitive to AP integral. The quantitative relationships established between resting potential, AP properties, AP conduction and Ca2+ transients provide the foundation for future studies of failure of ECC induced by depolarization of the resting potential.

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Section: Resultssupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

The role of action potential changes in depolarization-induced failure of excitation contraction coupling in mouse skeletal muscle

Wang

Nawaz

Dupont

et al. 2022

eLife

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“…For example, half-maximum Ca 2+ release occurs near −60 mV at 7.5 mM Ca 2+ and −90 mV at 0.010 mM Ca 2+ with no Ca 2+ release at −60 mV ( Brum et al, 1988b ). While in normal [Ca 2+ ] e and [K + ] e none of the Ca V 1.1 are inactivated in frog muscles, there is evidence that they are partially inactivated in mouse muscle ( Ferreira Gregorio et al, 2017 ); i.e., mouse muscles are expected to be more sensitive to changes in [Ca 2+ ] e than frog muscles. Therefore, a third mechanism for the depressive effect of low [Ca 2+ ] e on tetanic force may involve a hyperpolarizing shift for the inactivation of Ca V 1.1 and Ca 2+ release as less Ca 2+ is bound to Ca V 1.1.…”

Section: Discussionmentioning

confidence: 99%

Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles

Uwera

Ammar

McRae

et al. 2020

Journal of General Physiology

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Hyperkalemic periodic paralysis (HyperKPP) manifests as stiffness or subclinical myotonic discharges before or during periods of episodic muscle weakness or paralysis. Ingestion of Ca2+ alleviates HyperKPP symptoms, but the mechanism is unknown because lowering extracellular [Ca2+] ([Ca2+]e) has no effect on force development in normal muscles under normal conditions. Lowering [Ca2+]e, however, is known to increase the inactivation of voltage-gated cation channels, especially when the membrane is depolarized. Two hypotheses were tested: (1) lowering [Ca2+]e depresses force in normal muscles under conditions that depolarize the cell membrane; and (2) HyperKPP muscles have a greater sensitivity to low Ca2+-induced force depression because many fibers are depolarized, even at a normal [K+]e. In wild type muscles, lowering [Ca2+]e from 2.4 to 0.3 mM had little effect on tetanic force and membrane excitability at a normal K+ concentration of 4.7 mM, whereas it significantly enhanced K+-induced depression of force and membrane excitability. In HyperKPP muscles, lowering [Ca2+]e enhanced the K+-induced loss of force and membrane excitability not only at elevated [K+]e but also at 4.7 mM K+. Lowering [Ca2+]e increased the incidence of generating fast and transient contractures and gave rise to a slower increase in unstimulated force, especially in HyperKPP muscles. Lowering [Ca2+]e reduced the efficacy of salbutamol, a β2 adrenergic receptor agonist and a treatment for HyperKPP, to increase force at elevated [K+]e. Replacing Ca2+ by an equivalent concentration of Mg2+ neither fully nor consistently reverses the effects of lowering [Ca2+]e. These results suggest that the greater Ca2+ sensitivity of HyperKPP muscles primarily relates to (1) a greater effect of Ca2+ in depolarized fibers and (2) an increased proportion of depolarized HyperKPP muscle fibers compared with control muscle fibers, even at normal [K+]e.

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“…If it is removed, the voltage-sensor gating charges of the DHPR are shifted to an altered mode of mobility (termed charge 2) exhibiting slower kinetics in a more negative voltage range. In this mode, voltage sensing is no longer coupled to calcium release ( Brum et al, 1988a ; Ferreira Gregorio et al, 2017 ).…”

Section: The Role Of Extracellular Calcium In Skeletal Muscle Eccmentioning

confidence: 99%

ECC meets CEU—New focus on the backdoor for calcium ions in skeletal muscle cells

Melzer

2020

Journal of General Physiology

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The voltage sensor of excitation–contraction coupling in mammals: Inactivation and interaction with Ca2+

Cited by 12 publications

References 71 publications

The role of action potential changes in depolarization-induced failure of excitation contraction coupling in mouse skeletal muscle

The role of action potential changes in depolarization-induced failure of excitation contraction coupling in mouse skeletal muscle

Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles

ECC meets CEU—New focus on the backdoor for calcium ions in skeletal muscle cells

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