Insulin modulation of ATP-sensitive K + channel of rat skeletal muscle is impaired in the hypokalaemic state

Tricarico, Domenico; Capriulo, Raffaele; Camerino, Diana Conte

doi:10.1007/s004240050774

Cited by 19 publications

(25 citation statements)

References 20 publications

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“…It is impossible to calculate the concentration in the tissue close to the probe, because the dilution space and the amount carried away by the blood are unknown. If it is assumed that the released glibenclamide is diluted in 1 cm 3 of tissue, then the concentration after 1 min is 5 ϫ 10 Ϫ7 M, which is within the range reported in the literature (3,17,24) to be relevant for inhibition of KATP channels.…”

Section: Microdialysis Experimentsmentioning

confidence: 82%

“…However, inasmuch as the concentrations of these factors are low at rest, it is unlikely that they contribute to the opening of the K ATP channels. Insulin, on the other hand, is likely to be involved in the opening of K ATP channels at rest, inasmuch as insulin has been demonstrated to increase the K ATP current in patch-clamped rat muscle fibers (24,25).…”

Section: Importance Of K Atp Channelsmentioning

confidence: 99%

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Localization and function of ATP-sensitive potassium channels in human skeletal muscle

Nielsen¹,

Kristensen²,

Hellsten³

et al. 2003

American Journal of Physiology-Regulatory, Integrative and Comp

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Section: Microdialysis Experimentsmentioning

confidence: 82%

Section: Importance Of K Atp Channelsmentioning

confidence: 99%

Localization and function of ATP-sensitive potassium channels in human skeletal muscle

Nielsen¹,

Kristensen²,

Hellsten³

et al. 2003

American Journal of Physiology-Regulatory, Integrative and Comp

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“…This mechanism can explain the hypokalemia, the membrane depolarization, and the insulin-induced paralysis affecting patients with HOPP. This is supported by the finding that in the K + -depleted rats, insulin reduces the residual currents, aggravating the fiber depolarization and provoking paralysis (5,32), rather than inducing activation of the K ATP channel as it does in the normokalemic rats (7).…”

mentioning

confidence: 78%

Impairment of skeletal muscle adenosine triphosphate–sensitive K+ channels in patients with hypokalemic periodic paralysis

Tricarico

Servidei²,

Tonali³

et al. 1999

J. Clin. Invest.

100

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The adenosine triphosphate (ATP)-sensitive K + channel (K ATP ) is a metabolically regulated K + channel present in high density in different tissues, including skeletal muscle (1-4). Although in the last few years the role of this type of ion channel in cardiac and pancreatic β cells has been extensively investigated, not much is known about the role of the K ATP channel in the skeletal muscle. A recent report (5) suggested a possible role of this ion channel in muscle disorders related to hypokalemia. For example, we have shown that in the K + -depleted rat (6), in which a chronic hypokalemia was produced by feeding the rats with a K + -free diet, the activity of the sarcolemma K ATP channels is abnormally reduced. In these animals, the in vitro administration of insulin to the muscles abolishes the residual K ATP current and depolarizes the fibers (5). In contrast, in normokalemic rats, the hormone induces stimulation of the sarcolemma K ATP channels and hyperpolarizes the fibers (7,8). Similarly, in humans affected by an inherited muscle disorder known as hypokalemic periodic paralysis (HOPP; ref. 9), insulin produces fiber depolarization and muscle paralysis associated with a fall of the serum K + concentration (from 3.5 to <2 mEq; ref. 9) but produces fiber hyperpolarization in healthy subjects (7,9).Linkage studies have shown that the human HOPP gene maps to chromosome 1q31-32 and is colocalized with the gene encoding the α1 subunit of the skeletal muscle L-type Ca 2+ channel (10-14). Three point mutations were found within the coding sequence of the α1 subunit containing the dihydropyridine (DHP) receptor, resulting in arginine→histidine (R528H, R1239H) and arginine→glycine (R1239G) substitutions (14). However, functional studies have shown that these mutations do not significantly affect the macroscopic L-type Ca 2+ current of myotubes cultured from muscle of patients with HOPP, or the Ca 2+ current carried by channels expressed in the cell line (15-17). It has recently been proposed (17) that factor(s) directly or indirectly related to the DHP mutation play a role in the pathogenesis of HOPP. This poses the question of how the genotype is related to the phenotype of the muscle pathology (16-18). Indeed, although the mutations of the α1 subunit of the Ca 2+ channel have been found in two of three of the patients with HOPP, the link between the mutations of the DHP receptor, the depolarization of the fibers, the characteristic muscle paralysis induced by insulin, and the hypokalemia occurring during the attacks is not yet understood (17, 18). These clinical and laboratory findings suggest the possible involvement of the K ATP channel also in the pathogenesis of human HOPP. This is also supported by the observations that the K + channel openers, cromakalim and pinacidil, are, respectively, capable of repolarizing the skeletal muscle fibers from humans affected by HOPP and restoring the muscle strength in the same patients (18-22). Received for publication July 14, 1998, and accepted in revised form Januar...

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“…Studies in patients are limited for these rare disorders, and the intrinsic variability of symptoms often leads to ambiguous results (19). The K + -depleted rat preparation (20) or Ba 2+ -poisoned muscle fibers (16,21) have been used as surrogates of HypoPP, but there are no existing genetic models of HypoPP in mammals or lower animals. To address these issues, we developed a mouse model for HypoPP using a targeted mutation in Na V 1.4, homologous to the R669H reported for the first family with a HypoPP mutation located in SCN4A (8).…”

Section: Introductionmentioning

confidence: 99%

A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis

Burns³

et al. 2011

J. Clin. Invest.

109

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Hypokalemic periodic paralysis (HypoPP) is an ion channelopathy of skeletal muscle characterized by attacks of muscle weakness associated with low serum K + . HypoPP results from a transient failure of muscle fiber excitability. Mutations in the genes encoding a calcium channel (Ca V 1.1) and a sodium channel (Na V 1.4) have been identified in HypoPP families. Mutations of Na V 1.4 give rise to a heterogeneous group of muscle disorders, with gain-of-function defects causing myotonia or hyperkalemic periodic paralysis. To address the question of specificity for the allele encoding the Na V 1.4-R669H variant as a cause of HypoPP and to produce a model system in which to characterize functional defects of the mutant channel and susceptibility to paralysis, we generated knockin mice carrying the ortholog of the gene encoding the Na V 1.4-R669H variant (referred to herein as R669H mice). Homozygous R669H mice had a robust HypoPP phenotype, with transient loss of muscle excitability and weakness in low-K + challenge, insensitivity to high-K + challenge, dominant inheritance, and absence of myotonia. Recovery was sensitive to the Na + /K + -ATPase pump inhibitor ouabain. Affected fibers had an anomalous inward current at hyperpolarized potentials, consistent with the proposal that a leaky gating pore in R669H channels triggers attacks, whereas a reduction in the amplitude of action potentials implies additional loss-of-function changes for the mutant Na V 1.4 channels.

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Insulin modulation of ATP-sensitive K + channel of rat skeletal muscle is impaired in the hypokalaemic state

Cited by 19 publications

References 20 publications

Localization and function of ATP-sensitive potassium channels in human skeletal muscle

Localization and function of ATP-sensitive potassium channels in human skeletal muscle

Impairment of skeletal muscle adenosine triphosphate–sensitive K+ channels in patients with hypokalemic periodic paralysis

A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis

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