Pentylenetetrazol-induced seizures are associated with Na+,K+-ATPase activity decrease and alpha subunit phosphorylation state in the mice cerebral cortex

Marquezan, Bárbara P.; Funck, Vinícius Rafael; Oliveira, Clarissa Vasconcelos de; Pereira, Leticia; Araújo, Stífani Machado; Zarzecki, Micheli Stéfani; Royes, Luiz Fernando Freire; Furian, Ana Flávia; Oliveira, Mauro Schneider

doi:10.1016/j.eplepsyres.2013.03.007

Cited by 14 publications

(15 citation statements)

References 19 publications

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“…19 Decreases in Na þ , K þ -ATPase activity have been detected in animal models of epilepsy and in forms of human myoclonus epilepsy and mitochondrial disorders. [20][21][22] Moreover, pharmacologic inhibition of neuronal Na þ , K þ -ATPase by cardiac glycosides provokes seizures in rats, 23 and changes in membrane potential and epileptic bursting activity were detected after the blocking of Na þ , K þ -ATPase activity by ouabain in vitro. 24 Very recently, germline mutations in ATP1A1 have been reported in individuals with Charcot-Marie-Tooth type 2 disease (CMT2) [CMT2DD, MIM: 618036].…”

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confidence: 99%

Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability

Schlingmann

Bandulik

Mammen

et al. 2018

The American Journal of Human Genetics

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Over the last decades, a growing spectrum of monogenic disorders of human magnesium homeostasis has been clinically characterized, and genetic studies in affected individuals have identified important molecular components of cellular and epithelial magnesium transport. Here, we describe three infants who are from non-consanguineous families and who presented with a disease phenotype consisting of generalized seizures in infancy, severe hypomagnesemia, and renal magnesium wasting. Seizures persisted despite magnesium supplementation and were associated with significant intellectual disability. Whole-exome sequencing and conventional Sanger sequencing identified heterozygous de novo mutations in the catalytic Na þ , K þ-ATPase a1 subunit (ATP1A1). Functional characterization of mutant Na þ , K þ-ATPase a1 subunits in heterologous expression systems revealed not only a loss of Na þ , K þ-ATPase function but also abnormal cation permeabilities, which led to membrane depolarization and possibly aggravated the effect of the loss of physiological pump activity. These findings underline the indispensable role of the a1 isoform of the Na þ , K þ-ATPase for renal-tubular magnesium handling and cellular ion homeostasis, as well as maintenance of physiologic neuronal activity.

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confidence: 99%

Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability

Schlingmann

Bandulik

Mammen

et al. 2018

The American Journal of Human Genetics

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“…Protein kinase C (PKC) mediates the phosphorylation of ␣-subunit at Ser 11 , Ser 16 , or Ser 18 to enhance or repress the catalytic action of Na ϩ /K ϩ -ATPase in vertebrates (26 -30). Interest-ingly, in the rat Rattus norvegicus, PKC phosphorylation of ␣-subunit at Ser 23 corresponding to Ser 18 of the mature cleaved form stimulates its activity, whereas phosphorylation of ␣-subunit at Ser 943 by protein kinase A (PKA) inhibits its activity (31)(32)(33). The activity of Na ϩ /K ϩ -ATPase can be rapidly induced by hormones, including cortisol, growth hormone, insulin-like growth factor I, prolactin, thyroid hormones, and steroids (34).…”

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confidence: 99%

Protein kinase C mediates juvenile hormone–dependent phosphorylation of Na+/K+-ATPase to induce ovarian follicular patency for yolk protein uptake

Jing

Zhang

et al. 2018

Journal of Biological Chemistry

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In oviparous animals, vitellogenesis is prerequisite to egg production and embryonic growth after oviposition. For successful insect vitellogenesis and oogenesis, vitellogenin (Vg) synthesized in the fat body (homologue to vertebrate liver and adipose tissue) must pass through the intercellular channels, a condition known as patency in the follicular epithelium, to reach the surface of oocytes. This process is controlled by juvenile hormone (JH) in many insect species, but the underlying mechanisms remain elusive. Previous work has suggested the possible involvement of Na ؉ /K ؉ -ATPase in patency initiation, but again, the regulatory cascade of Na ؉ /K ؉ -ATPase for patency initiation has been lacking. Using the migratory locust Locusta migratoria as a model system, we report here that RNAi-mediated knockdown of gene coding for Na ؉ /K ؉ -ATPase, inhibition of its phosphorylation, or suppression of its activity causes loss of patency, resulting in blocked Vg uptake, arrested oocyte maturation, and impaired ovarian growth. JH triggers G proteincoupled receptor (GPCR), receptor tyrosine kinase (RTK), phospholipase C (PLC), inositol trisphosphate receptor (IP3R), and protein kinase C (PKC) to phosphorylate Na ؉ /K ؉ -ATPase ␣-subunit at amino acid residue Ser 8 , consequently activating Na ؉ /K ؉ -ATPase for the induction of patency in vitellogenic follicular epithelium. Our results thus point to a previously unidentified mechanism by which JH induces the phosphorylation and activation of Na ؉ /K ؉ -ATPase via a signaling cascade of GPCR, RTK, PLC, IP3R, and PKC. The findings advance our understanding of JH regulation in insect vitellogenesis and oogenesis.

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“…Pentylenetetrazole injection is one of the most commonly used protocols to investigate new strategies to counteract the consequences of excessive brain excitability, including convulsive seizures [23][24][25]. Seizure latency and duration can be used as surrogate markers for determining the efficiency of specific drugs on modulating abnormal excitability after PTZ administration [26].…”

Section: Discussionmentioning

confidence: 99%

“…The convulsive agent PTZ (60 mg/kg; Sigma-Aldrich, Cambridge, UK) was diluted in saline and administered intraperitoneally (i.p.) [23].…”

Section: Methodsmentioning

confidence: 99%

“…Immediately after PTZ injections, the mice were monitored for 15 min. and the behavioural seizures' latency and duration were recorded [23]. Seizures were defined by the occurrence of generalized tonic-clonic seizures beginning with running, followed by the loss of posture control, then a short tonic phase (flexion or extension of fore and hind limbs) progressing to the clonus of all four limbs.…”

Section: Methodsmentioning

confidence: 99%

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Anticonvulsant Effects of N‐Arachidonoyl‐Serotonin, a Dual Fatty Acid Amide Hydrolase Enzyme and Transient Receptor Potential Vanilloid Type‐1 (TRPV1) Channel Blocker, on Experimental Seizures: The Roles of Cannabinoid CB1 Receptors and TRPV1 Channels

Vilela

Medeiros

Oliveira

et al. 2014

Basic Clin Pharma Tox

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Selective blockade of anandamide hydrolysis, through the inhibition of the FAAH enzyme, has anticonvulsant effects, which are mediated by CB1 receptors. Anandamide, however, also activates TRPV1 channels, generally with an opposite outcome on neuronal modulation. Thus, we suggested that the dual FAAH and TRPV1 blockade with N-arachidonoyl-serotonin (AA-5-HT) would be efficacious in inhibiting pentylenetetrazole (PTZ)-induced seizures in mice. We also investigated the contribution of CB1 activation and TRPV1 blockade to the overt effect of AA-5-HT. In the first experiment, injection of AA-5-HT (0.3-3.0 mg/kg) delayed the onset and reduced the duration of PTZ (60 mg)-induced seizures in mice. These effects were reversed by pre-treatment with the CB1 antagonist, AM251 (1.0-3.0 mg/kg). Finally, we observed that administration of the selective TRPV1 antagonist, SB366791 (0.1-1 mg/kg), did not entirely mimic AA-5-HT effects. In conclusion, AA-5-HT alleviates seizures in mice, an effect inhibited by CB1 antagonism, but not completely mimicked by TRPV1 blockage, indicating that the overall effect of AA-5-HT seems to depend mainly on CB1 receptors. This may represent a new strategy for the development of drugs against seizures, epilepsies and related syndromes.The endocannabinoid arachidonoyl ethanolamide (anandamide) is involved in the modulation of several neurophysiological processes, including nociception, memory, pain and convulsive seizures [1,2]. In the nervous system, anandamide is synthesized and released as a neurotransmitter from membrane lipids [3]. Its actions are terminated by hydrolysis mediated by fatty acid amide hydrolase (FAAH) [4], an enzyme highly expressed in several brain regions [5]. Accordingly, enhancement of anandamide signalling can be achieved by selective inhibition of FAAH activity [6].The primary target for anandamide is the type 1 cannabinoid (CB1) receptor, a metabotropic receptor mainly coupled to a Gi protein [7]. Another proposed target is the transient receptor potential vanilloid type-1 channel (TRPV1) [8][9][10][11]. This receptor is activated by heat (>43°C), low pH and the pungent ingredient of hot chilli peppers, capsaicin, as well as anandamide [8,12]. Indeed, TRPV1 and CB1 are co-expressed in several brain regions, including the hypothalamus, cerebellum, cerebral cortex, striatum, midbrain, hippocampus and substantia nigra, although they may have opposite roles in modulating neural activity [13][14][15][16]. For instance, in contrast to CB1 receptor, TRPV1 activation promotes calcium influx, firing rate and glutamate release, facilitating long-term potentiation and suppressing long-term depression. Such changes could be associated with the enhancement of synaptic efficiency and may be important in epileptogenesis [17,18].Anticonvulsant properties mediated through the activation of cannabinoid CB1 receptors have been observed in different experimental seizure models, in which anandamide is produced on-demand to restrain excitotoxicity [19][20][21]. Recently, it has be...

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Pentylenetetrazol-induced seizures are associated with Na+,K+-ATPase activity decrease and alpha subunit phosphorylation state in the mice cerebral cortex

Cited by 14 publications

References 19 publications

Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability

Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability

Protein kinase C mediates juvenile hormone–dependent phosphorylation of Na+/K+-ATPase to induce ovarian follicular patency for yolk protein uptake

Anticonvulsant Effects of N‐Arachidonoyl‐Serotonin, a Dual Fatty Acid Amide Hydrolase Enzyme and Transient Receptor Potential Vanilloid Type‐1 (TRPV1) Channel Blocker, on Experimental Seizures: The Roles of Cannabinoid CB1 Receptors and TRPV1 Channels

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