Properties of Na<sup>+</sup>currents conducted by a skeletal muscle L-type Ca<sup>2+</sup>channel pore mutant (SkEIIIK)

Bannister, Roger A.; Beam, Kurt G.

doi:10.4161/chan.5.3.15269

Cited by 8 publications

(20 citation statements)

References 34 publications

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“…A number of publications (11)(12)(13)(14)22) have described L-type Ca 2þ channels as having three gating modes: mode 0 (deeply closed), mode 1 (brief openings), and mode 2 (long openings). Additionally, it has been proposed that there is a reversible transition between mode 0 and mode 1, between mode 1 and mode 2, and also between mode 0 and mode 2 (see (12 and 14), for detailed descriptions).…”

Section: Discussionmentioning

confidence: 99%

Impaired Gating of an L-Type Ca2+ Channel Carrying a Mutation Linked to Malignant Hyperthermia

Bannister

Beam

2013

Biophysical Journal

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Recently, we characterized the functional properties of a mutant skeletal muscle L-type Ca(2+) channel (CaV1.1 R174W) linked to the pharmacogenetic disorder malignant hyperthermia. Although the R174W mutation neutralizes the innermost basic amino acid in the voltage-sensing S4 helix of the first conserved membrane repeat of CaV1.1, the ability of the mutant channel to engage excitation-contraction coupling was largely unaffected by the introduction of the bulky tryptophan residue. In stark contrast, the mutation ablated the ability of CaV1.1 to produce L-type current under our standard recording conditions. In this study, we have investigated the mechanism of channel dysfunction more extensively. We found that CaV1.1 R174W will open and conduct Ca(2+) in response to strong or prolonged depolarizations in the presence of the 1,4-dihydropyridine receptor agonist ±Bay K 8644. From these results, we have concluded that the R174W mutation impedes entry into both mode 1(low Po) and mode 2 (high Po) gating states and that these gating impairments can be partially overcome by maneuvers that promote entry into mode 2.

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Section: Discussionmentioning

confidence: 99%

Impaired Gating of an L-Type Ca2+ Channel Carrying a Mutation Linked to Malignant Hyperthermia

Bannister

Beam

2013

Biophysical Journal

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“…The EK mutation abolished inward L-type Ca 2+ currents, but permitted outward monovalent Cs + currents. The permeation of EK channels to monovalent cations (for example, Cs + and Na + ; [ 30 ]) is unlikely to alter resting membrane because the EK monovalent cation conductance is only activated at depolarized potentials. Also, since the activation kinetics of EK channels is slow [ 2 , 30 ] relative to the duration of the skeletal muscle action potential, Na + flux through EK channels should be minimal, and thus unlikely to alter action potential properties or intracellular Na + levels (approximately 10 mM).…”

Section: Resultsmentioning

confidence: 99%

“…The permeation of EK channels to monovalent cations (for example, Cs + and Na + ; [ 30 ]) is unlikely to alter resting membrane because the EK monovalent cation conductance is only activated at depolarized potentials. Also, since the activation kinetics of EK channels is slow [ 2 , 30 ] relative to the duration of the skeletal muscle action potential, Na + flux through EK channels should be minimal, and thus unlikely to alter action potential properties or intracellular Na + levels (approximately 10 mM). The magnitude and decay kinetics of voltage-gated Ca 2+ transients (assessed using a low affinity Ca 2+ indicator, mag-fluo-4 AM) elicited by a low frequency train of electrical stimulation (1 Hz) were not significantly different between FDB fibers from WT and EK mice (Figure 1 C-F), demonstrating that ECC was not altered by the EK mutation.…”

Section: Resultsmentioning

confidence: 99%

Ca2+ permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca2+ signaling to sustain muscle function

et al. 2015

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BackgroundCa2+ influx through CaV1.1 is not required for skeletal muscle excitation-contraction coupling, but whether Ca2+ permeation through CaV1.1 during sustained muscle activity plays a functional role in mammalian skeletal muscle has not been assessed.MethodsWe generated a mouse with a Ca2+ binding and/or permeation defect in the voltage-dependent Ca2+ channel, CaV1.1, and used Ca2+ imaging, western blotting, immunohistochemistry, proximity ligation assays, SUnSET analysis of protein synthesis, and Ca2+ imaging techniques to define pathways modulated by Ca2+ binding and/or permeation of CaV1.1. We also assessed fiber type distributions, cross-sectional area, and force frequency and fatigue in isolated muscles.ResultsUsing mice with a pore mutation in CaV1.1 required for Ca2+ binding and/or permeation (E1014K, EK), we demonstrate that CaV1.1 opening is coupled to CaMKII activation and refilling of sarcoplasmic reticulum Ca2+ stores during sustained activity. Decreases in these Ca2+-dependent enzyme activities alter downstream signaling pathways (Ras/Erk/mTORC1) that lead to decreased muscle protein synthesis. The physiological consequences of the permeation and/or Ca2+ binding defect in CaV1.1 are increased fatigue, decreased fiber size, and increased Type IIb fibers.ConclusionsWhile not essential for excitation-contraction coupling, Ca2+ binding and/or permeation via the CaV1.1 pore plays an important modulatory role in muscle performance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-014-0027-1) contains supplementary material, which is available to authorized users.

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“…Conversely, in the E1014K mouse model, the E to K charge conversion in repeat III leads to impairment of the Ca 2+ selectivity filter, enabling only low-affinity (mM) Ca 2+ binding to the pore 32 , 33 . Thus, the E1014K-DHPR does not allow Ca 2+ permeation but shows a strong conductivity for monovalent cations 31 , 32 , which consequently turns it into a junctionally targeted, slowly activating, non-inactivating Na + channel 34 .…”

Section: Discussionmentioning

confidence: 99%

“…The authors concluded that Ca 2+ permeation and/or binding via/to the DHPR pore plays an important modulatory role in muscle performance 31 . However, a drawback of this interpretation is the negligence of the presence of a persisting permeation of monovalent cations through the mutant EK channel 31 , 32 , 34 , which might, for instance, affect the membrane potential during muscle activity 32 .…”

Section: Introductionmentioning

confidence: 99%

The Ca2+ influx through the mammalian skeletal muscle dihydropyridine receptor is irrelevant for muscle performance

et al. 2017

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Skeletal muscle excitation–contraction (EC) coupling is initiated by sarcolemmal depolarization, which is translated into a conformational change of the dihydropyridine receptor (DHPR), which in turn activates sarcoplasmic reticulum (SR) Ca2+ release to trigger muscle contraction. During EC coupling, the mammalian DHPR embraces functional duality, as voltage sensor and l-type Ca2+ channel. Although its unique role as voltage sensor for conformational EC coupling is firmly established, the conventional function as Ca2+ channel is still enigmatic. Here we show that Ca2+ influx via DHPR is not necessary for muscle performance by generating a knock-in mouse where DHPR-mediated Ca2+ influx is eliminated. Homozygous knock-in mice display SR Ca2+ release, locomotor activity, motor coordination, muscle strength and susceptibility to fatigue comparable to wild-type controls, without any compensatory regulation of multiple key proteins of the EC coupling machinery and Ca2+ homeostasis. These findings support the hypothesis that the DHPR-mediated Ca2+ influx in mammalian skeletal muscle is an evolutionary remnant.

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Properties of Na⁺currents conducted by a skeletal muscle L-type Ca²⁺channel pore mutant (SkEIIIK)

Cited by 8 publications

References 34 publications

Impaired Gating of an L-Type Ca2+ Channel Carrying a Mutation Linked to Malignant Hyperthermia

Impaired Gating of an L-Type Ca2+ Channel Carrying a Mutation Linked to Malignant Hyperthermia

Ca2+ permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca2+ signaling to sustain muscle function

The Ca2+ influx through the mammalian skeletal muscle dihydropyridine receptor is irrelevant for muscle performance

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Properties of Na+currents conducted by a skeletal muscle L-type Ca2+channel pore mutant (SkEIIIK)

Cited by 8 publications

References 34 publications

Impaired Gating of an L-Type Ca2+ Channel Carrying a Mutation Linked to Malignant Hyperthermia

Impaired Gating of an L-Type Ca2+ Channel Carrying a Mutation Linked to Malignant Hyperthermia

Ca2+ permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca2+ signaling to sustain muscle function

The Ca2+ influx through the mammalian skeletal muscle dihydropyridine receptor is irrelevant for muscle performance

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Properties of Na⁺currents conducted by a skeletal muscle L-type Ca²⁺channel pore mutant (SkEIIIK)