Modulation of ATP-Sensitive K+Channel by Insulin in Rat Skeletal Muscle Fibers

doi:10.1006/bbrc.1997.6320

Biochemical and Biophysical Research Communications

Volume 232, Issue 2, 17 March 1997, Pages 536-539

https://doi.org/10.1006/bbrc.1997.6320 Get rights and content

Abstract

In the present study we evaluated the modulation of the sarcolemmal ATP sensitive K⁺channel by insulin. The “in vivo” administration of insulin to the rats led to an hyperpolarization of the skeletal muscle fibers. This effect is antagonized by “in vitro” incubation of the muscle with glybenclamide, an ATP sensitive K⁺channel blocker. Patch clamp experiments revealed that insulin enhanced the mean current of the ATP sensitive K⁺channel by a factor of 1.4. This effect is mediated by an increase of the channel open probability, while no change occurred in the single channel conductance nor in the channel density. In the treated rats, the sensitivity of the channel to ATP and glybenclamide is abnormally reduced. Our results are consistent with an activation of the ATP sensitive K⁺channel by insulin. This contributes to the hyperpolarization of the skeletal muscle fibers.

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Opening/blocking actions of pyruvate kinase antibodies on neuronal and muscular KATP channels
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Several studies have shown that ATP-sensitive K+ (KATP) channels can be associated with glycolytic proteins including pumps and enzymes to form macromolecular complexes that contribute to the channels regulation [7]. For example, in cardiac and skeletal muscle fibres as in pancreatic beta cells and epithelial cells, KATP channels are structurally and functionally coupled with the 3Na+/2K+ATP-ase pump [8–11]. In cardiac myocytes, it has been demonstrated that KATP channels are associated with metabolic enzymes such as adenylate kinase (AK) and creatine kinase (CK), lactate dehydrogenase (LDH) and pyruvate kinase (PK).
ATP-sensitive-K⁺ (KATP) channels couple metabolism to the electrical activity of the cells. This channel is associated with glycolytic enzymes to form complexes regulating the channel activity in various tissues. The pyruvate-kinase (PK) enzyme is an antigen in the Paediatric Autoimmune Neuropsychiatric Disorders Associated Streptococcal infection known as PANDAS which is characterized by an abnormal production of auto-antibodies against PK. Here, the effects of the anti-pyruvate kinase antibody (anti-PK-ab) on the muscle and neuronal KATP channels were investigated in native rat skeletal muscle fibres and human neuroblastoma cell-line (SH-SY5Y), respectively. Furthermore, the interaction of PK with the inwardly rectifier potassium channel (Kir6.1/Kir6.2) subunits of the KATP channels was investigated by co-immunoprecipitation experiments in mouse brain using the anti-PK-ab. Patch-clamp experiments showed that the short-term incubation (1 h) of the fibres with the anti-PK-ab at the dilutions of 1:500 and 1:300 enhanced the KATP current of 19.6% and 33.5%, respectively. As opposite, the long-term incubation (24 h) of the fibres with the anti-PK-ab at the dilutions of 1:500 and 1:300 reduced the KATP current of 16% and 24%, respectively, reducing the diameter with atrophy. The direct application of the anti-PK-ab to the excised patches in the absence of intracellular ATP caused channel block, while in the presence of nucleotide channel opened. In neuronal cell line, in the short-term the anti-PK-ab potentiated KATP currents without affecting survival, while in the long-term the anti-PK-ab reduced KATP currents inducing neuronal death. Opening/blocking actions of the anti-PK antibodies on the KATP channels were observed, the blocking action causes fibre atrophy and neuronal death. We demonstrated that PK and Kir subunits are physically/functionally coupled in neurons. The KATP/PK complex can be proposed a novel target in the autoimmune diseases associated with anti-PK production as in PANDAS.
Cardiac, Skeletal, and Smooth Muscle Regulation by Ghrelin
2007, Vitamins and Hormones
Citation Excerpt :
This reverse of Cl− conductivity was shown to be resulted from the okadaic acid‐sensitive phosphatase that counteracts the abnormally elevated PKC activity responsible for the inhibition of Cl− channels (De Luca et al., 1997). Also the recovery of the K+ conductivity promoted by the GH/IGF‐1 axis is dependent on the normalization of the intracellular Ca2+ level that is affected in this process (Tricarico et al., 1997b). Pierno et al. (2003) postulated that ghrelin might possess the same effect as GH in reversing age effects in the skeletal muscle.
Ghrelin, mainly secreted from gastric mucosa, is the endogenous ligand for the growth hormone secretagogue receptor and induces a potent release of growth hormone. Ghrelin is widely expressed in different tissues and therefore has both endocrine and paracrine/autocrine effects. In this chapter, we summarize: (1) structure and distribution of ghrelin and its receptors; (2) myocardial effects of ghrelin, describing its acute and chronic actions on cardiac function; (3) ghrelin effects on smooth muscle, namely vascular smooth muscle, intraocular and gastrointestinal smooth muscle; and (4) skeletal actions of ghrelin. Ghrelin has a potent vasodilator effect, thereby reducing cardiac afterload and increasing cardiac output. In models of heart failure and myocardial ischemia, ghrelin administration has beneficial effects. At smooth muscle, ghrelin modulates vascular tone, increases gut transit, and relaxes iris muscles. In the skeletal muscle, ghrelin regulates resting membrane potential. In conclusion, there are increasing evidences that ghrelin is a peptide with paracrine actions that can modulate cardiac, smooth, and skeletal muscle functions.
Effect of chronic insulin on cromakalim-induced relaxation in established streptozotocin-diabetic rat basilar artery
2004, European Journal of Pharmacology
Our goals were to determine whether the response of the rat isolated basilar artery to activation of ATP-sensitive potassium (K_ATP) channels is altered in diabetes mellitus, and to determine the effect of chronic insulin treatment on this response in established diabetic rats. The relaxation induced by cromakalim, an activator of K_ATP channels, was significantly weaker in insulin-untreated streptozotocin-induced diabetic rats than in the controls. This impairment was significantly improved following chronic administration of insulin. The relaxations induced by two Ca²⁺-activated K⁺-channel activators [1-ethyl-2-benzimidazolinone (1-EBIO) or 1, 3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619)] were not significantly different between control and insulin-untreated diabetic rats. The sodium nitroprusside-induced relaxation was similar among the three groups (control, diabetic, and insulin-treated diabetic). These results suggest that: (a) the impaired cromakalim-induced relaxation seen in diabetic rats is not due to a nonspecific effect of diabetes mellitus on vasorelaxation, but at least partly to an effect on K_ATP channels, and (b) that this impaired relaxation can be restored by chronic insulin treatment.
Involvement of 3Na+/2K+ ATP-ase and Pi-3 kinase in the response of skeletal muscle ATP-sensitive K+ channels to insulin
2003, Neuromuscular Disorders
The modulation of ATP-sensitive K⁺ channel (K_ATP) by insulin plays a role in neuromuscular disorders associated to altered K⁺ homeostasis. However, the mechanisms by which insulin modulates K_ATP channels are not known. Here, the insulin-dependent 3Na⁺/2K⁺ ATP-ase and Pi-3 kinase pathways were explored by using patch-clamp techniques. High and low affinity inhibition of K_ATP channels by ouabain was observed in the insulin-stimulated and resting fibers, respectively. The 9A5 antibody directed against the α1-subunit of the pump inhibited the K_ATP channel in the resting fibers but fails to inhibit it in the insulin-stimulated fibers. In contrast, the RT2NKATPabr, an α2-subunit specific antibody, inhibited the K_ATP channels in the insulin-stimulated fibers failing to inhibit it in the resting fibers. The insulin-dependent stimulation of K_ATP channel was prevented by Pi-3 kinase inhibitors Wortmannin and LY294002. In conclusion, insulin stimulating the 3Na⁺/2K⁺ ATP-ase activates K_ATP channels through a membrane-delimited interaction thus controlling the K⁺ homeostasis. The Pi-3 kinase is the intracellular insulin signal linking the glucose homeostasis to the K_ATP channel.
Cognitive effects of insulin in the central nervous system
2001, Neuroscience and Biobehavioral Reviews
Evidence has been accumulating recently that the hormone insulin may modulate cognitive activity by acting in the central nervous system. Initially derived from the observation that insulin and insulin receptors are found in specific brain areas, this evidence also includes cognitive assessments of humans in insulin-deficient and insulin-resistant disease states and experimental manipulation of rodent models. Additional support is derived from in vivo and in vitro systems that are used to investigate the neurophysiological basis of learning and memory. This article is a brief review of the literature that suggests a connection between insulin and memory and draws together some of the findings relevant to possible physiological mechanisms for this cognitive effect.
Intracerebroventricular insulin enhances memory in a passive-avoidance task
2000, Physiology and Behavior
Previous studies have indicated a possible enhancing effect of hyperinsulinemia on certain cognitive tasks in human subjects. Further, brain areas important in these tasks have high concentrations of insulin receptors, suggesting that insulin might modulate memory by activity at specific central sites. Extending this observation to the laboratory rat would provide a convenient model system for determining factors important for this possible cognitive effect. The present experiment determined whether intracerebroventricular administration of insulin improves memory formation in rats. Long–Evans rats were trained on a step-through passive–avoidance task, in which they were either shocked or not after entering a darkened compartment. After training, the animals received an intracerebroventricular injection of 4 mU insulin, heat-deactivated insulin or saline vehicle. After 24 h, the animals were tested for retention of the task. Rats receiving insulin after being shocked had an increased latency to enter the dark compartment, compared to those rats that had received saline or heat-deactivated insulin after shock. This difference is consistent with an enhanced memory for the negative consequences of entering.

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^☆: Abbreviations used: K_ATP, ATP sensitive K⁺channelMOPS, 3-(N-morpholino) propanesulfonic acid; ATP, adenosine triphosphate; ADP, adenosine diphosphate; UDP, uridine diphosphate; EGTA, ethylene glycol bis(β-aminoethyl ether)-N, N, N′, N-tetraacetic acid; i.p., intraperitoneally; EDL, extensor digitorum longus muscle; FDB, flexor digitorum brevis muscle; P_open, channel open probability; γ, single channel conductance; N, number of functional channel; I, mean current; IC₅₀, concentration of the blockers required to produce a 50% decrease ofI.;

^☆☆: A. G. EngelC. Franzini-Armstrong, Eds.

¹: Corresponding author: Prof. D. Conte Camerino, Dipartimento Farmacobiologico, Facolta’ di Farmacia via Orabona n°4, 70126 Universita’ di Bari, Italia. Fax: 080-5442050.

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Biochemical and Biophysical Research Communications

Abstract

References (21)

TINS

Biochem. Biophys. Acta

Pflügers Arch.

Am. J. Physiol.

Endocrine Rev.

J. Bioenerg. Biomemb.

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Nature (Lond.)

Am. J. Physiol.

Cited by (32)

Opening/blocking actions of pyruvate kinase antibodies on neuronal and muscular KATP channels

Cardiac, Skeletal, and Smooth Muscle Regulation by Ghrelin

Effect of chronic insulin on cromakalim-induced relaxation in established streptozotocin-diabetic rat basilar artery

Involvement of 3Na<sup>+</sup>/2K<sup>+</sup> ATP-ase and Pi-3 kinase in the response of skeletal muscle ATP-sensitive K<sup>+</sup> channels to insulin

Cognitive effects of insulin in the central nervous system

Intracerebroventricular insulin enhances memory in a passive-avoidance task

Regular ArticleModulation of ATP-Sensitive K+Channel by Insulin in Rat Skeletal Muscle Fibers☆,☆☆

Abstract

TINS

Biochem. Biophys. Acta

Pflügers Arch.

Am. J. Physiol.

Endocrine Rev.

J. Bioenerg. Biomemb.

J. Neurol. Neurosurg. Psychiatr.

Pflügers Arch.

Nature (Lond.)

Am. J. Physiol.

Regular Article
Modulation of ATP-Sensitive K⁺Channel by Insulin in Rat Skeletal Muscle Fibers☆,☆☆