Calcium currents and asymmetric charge movement in malignant hyperpyrexia

Lamb, Graham D.; Hopkinson, K.C.; Denborough, M. A.

doi:10.1002/mus.880120208

Cited by 13 publications

(7 citation statements)

References 18 publications

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“…2 and Table II). In an earlier study describing charge movements in swine R615C Hom fibers, Lamb et al (1989) did not observe a shift in charge movement. Recently, however, Andronache et al (2009) reported a hyperpolarizing shift of ∼5 mV in charge movements of Y522S Het fibers.…”

Section: Discussionmentioning

confidence: 72%

“…2) is probably one contributor to the reduction in [ΔF/F] max . Interestingly, Lamb et al (1989) also found a reduction in Q max (∼20%) in swine R615C Hom gracilis fibers. Moreover, Andronache et al (2009) found an ∼10% reduction in Q max in Y522S Het interosseus fibers.…”

Section: Discussionmentioning

confidence: 79%

“…2 and Table II). In an earlier study describing charge movements in swine R615C Hom fibers, Lamb et al (1989) Figure 5. Steady-state inactivation of L-type current in WT and R163C MHS myotubes.…”

Section: Discussionmentioning

confidence: 99%

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A malignant hyperthermia–inducing mutation in RYR1 (R163C): consequent alterations in the functional properties of DHPR channels

Bannister

Estève

Eltit

et al. 2010

Journal of General Physiology

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Bidirectional communication between the 1,4-dihydropyridine receptor (DHPR) in the plasma membrane and the type 1 ryanodine receptor (RYR1) in the sarcoplasmic reticulum (SR) is responsible for both skeletal-type excitation–contraction coupling (voltage-gated Ca2+ release from the SR) and increased amplitude of L-type Ca2+ current via the DHPR. Because the DHPR and RYR1 are functionally coupled, mutations in RYR1 that are linked to malignant hyperthermia (MH) may affect DHPR activity. For this reason, we investigated whether cultured myotubes originating from mice carrying an MH-linked mutation in RYR1 (R163C) had altered voltage-gated Ca2+ release from the SR, membrane-bound charge movement, and/or L-type Ca2+ current. In myotubes homozygous (Hom) for the R163C mutation, voltage-gated Ca2+ release from the SR was substantially reduced and shifted (∼10 mV) to more hyperpolarizing potentials compared with wild-type (WT) myotubes. Intramembrane charge movements of both Hom and heterozygous (Het) myotubes displayed hyperpolarizing shifts similar to that observed in voltage-gated SR Ca2+ release. The current–voltage relationships for L-type currents in both Hom and Het myotubes were also shifted to more hyperpolarizing potentials (∼7 and 5 mV, respectively). Compared with WT myotubes, Het and Hom myotubes both displayed a greater sensitivity to the L-type channel agonist ±Bay K 8644 (10 µM). In general, L-type currents in WT, Het, and Hom myotubes inactivated modestly after 30-s prepulses to −50, −10, 0, 10, 20, and 30 mV. However, L-type currents in Hom myotubes displayed a hyperpolarizing shift in inactivation relative to L-type currents in either WT or Het myotubes. Our present results indicate that mutations in RYR1 can alter DHPR activity and raise the possibility that this altered DHPR function may contribute to MH episodes.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 79%

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A malignant hyperthermia–inducing mutation in RYR1 (R163C): consequent alterations in the functional properties of DHPR channels

Bannister

Estève

Eltit

et al. 2010

Journal of General Physiology

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“…Similarly, our group observed about a 7 mV hyperpolarizing shift in L-type current activation for mouse myotubes homozygous for the engineered R163C mutation [96]. Hyperpolarizing shifts in charge movement have also been observed for both R163C myotubes [96] and Y522S fibers [95], but not in swine R165C myotubes [97]. In regard to EC coupling, each of these malignant hyperthermia models [R163C, Y522S, R615C; 94-96,98,99] and dyspedic myotubes expressing RyR1 constructs carrying a number of different malignant hyperthermia-linked mutations [100] have also displayed hyperpolarizing shifts in SR Ca 2+ release in response to depolarization suggesting that RyR1 malignant hyperthermia mutations shift the equilibrium of Ca V 1.1 towards the state(s) active for EC coupling and L-type channel activation.…”

Section: Cav11 Channel Properties Are Atypically Dependent On Conformentioning

confidence: 88%

CaV1.1: The atypical prototypical voltage-gated Ca2+ channel

Bannister

Beam

2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

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CaV1.1 is the prototype for the other nine known CaV channel isoforms, yet it has functional properties that make it truly atypical of this group. Specifically, CaV1.1 is expressed solely in skeletal muscle where it serves multiple purposes; it is the voltage sensor for excitation-contraction (EC) coupling and it is an L-type Ca2+ channel which contributes to a form of activity-dependent Ca2+ entry that has been termed Excitation-Coupled Ca2+ Entry (ECCE). The ability of CaV1.1 to serve as voltage-sensor for EC coupling appears to be unique amongst CaV channels, whereas the physiological role of its more conventional function as a Ca2+ channel has been a matter of uncertainty for nearly 50 years. In this chapter, we discuss how CaV1.1 supports EC coupling, the possible relevance of Ca2+ entry through CaV1.1 and how alterations of CaV1.1 function can have pathophysiological consequences.

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“…Although the concentration of thymol is relatively low (0.01 %) in the original halothane-thymol mixture [17], its concentration may dramatically increase due to accumulation of thymol in the vaporizer. Indeed, halothane was shown to block Ca and K currents in cardiac [18-20] and skeletal [21] muscle membranes. These effects, obtained with liquid halothane (containing also thymol) in various preparations, strongly resemble the present results and also those of Magyar et al obtained in canine cardiac cells with thymol [9].…”

Section: Discussionmentioning

confidence: 99%

Effect of thymol on kinetic properties of Ca and K currents in rat skeletal muscle

et al. 2003

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Background: Thymol is widely used as a general antiseptic and antioxidant compound in the medical practice and industry, and also as a stabilizer to several therapeutic agents, including halothane. Thus intoxication with thymol may occur in case of ingestion or improper anesthesia. In the present study, therefore, concentration-dependent effects of thymol (30-600 micro-grams) were studied on calcium and potassium currents in enzymatically isolated rat skeletal muscle fibers using the double vaseline gap voltage clamp technique.

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Calcium currents and asymmetric charge movement in malignant hyperpyrexia

Cited by 13 publications

References 18 publications

A malignant hyperthermia–inducing mutation in RYR1 (R163C): consequent alterations in the functional properties of DHPR channels

A malignant hyperthermia–inducing mutation in RYR1 (R163C): consequent alterations in the functional properties of DHPR channels

CaV1.1: The atypical prototypical voltage-gated Ca2+ channel

Effect of thymol on kinetic properties of Ca and K currents in rat skeletal muscle

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