Neuronal carbonic anhydrase VII provides GABAergic excitatory drive to exacerbate febrile seizures

Ruusuvuori, Eva; Huebner, Antje K.; Kirilkin, Ilya; Yukin, Alexey Y.; Blaesse, Peter; Helmy, Mohamed M.; Kang, Hyo Jung; Muayed, Malek El; Hennings, J. Christopher; Voipio, Juha; Šestan, Nenad; Hübner, Christian A.; Kaila, Kai

doi:10.1038/emboj.2013.160

Cited by 80 publications

(96 citation statements)

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“…Such stimulation causes intense interneuronal firing, a consequent HCO 3 − -dependent increase in [Cl − ] i and a large depolarizing shift in DF GABA in the target pyramidal neurons, which is sufficient for the activation of NMDA receptors (NMDARs) 1,202 . Because CO 2 readily permeates neuronal membranes, intraneuronal HCO 3 − that is lost owing to net efflux through GABA A Rs is replenished by the activity of cytosolic carbonic anhydrases 193,204 (Supplementary information S2 (text)). Under these conditions, the increase in [Cl − ] i leads to enhanced K + –Cl − extrusion by KCC2, and to a consequent increase in [K + ] o , which further depolarizes both neurons and glia in a non-synaptic manner 101 (FIG.…”

Section: Cccs Control Ionic Plasticitymentioning

confidence: 99%

“…The mechanisms described above are likely to promote tetanus-induced long-term potentiation 203 as well as highly synchronized spontaneous network events, including seizures (see REFS 15,204), and may contribute to neuropathic pain 205 . Notably, carbonic anhydrase inhibitors, which are well known for their anticonvulsant actions, strongly inhibit activity-dependent E Cl shifts and GABAergic excitation in slice preparations 100,101 and reduce neuropathic pain 206,207 .…”

Section: Cccs Control Ionic Plasticitymentioning

confidence: 99%

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Cation-chloride cotransporters in neuronal development, plasticity and disease

et al. 2014

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Electrical activity in neurons requires a seamless functional coupling between plasmalemmal ion channels and ion transporters. Although ion channels have been studied intensively for several decades, research on ion transporters is in its infancy. In recent years, it has become evident that one family of ion transporters, cation-chloride cotransporters (CCCs), and in particular K+–Cl− cotransporter 2 (KCC2), have seminal roles in shaping GABAergic signalling and neuronal connectivity. Studying the functions of these transporters may lead to major paradigm shifts in our understanding of the mechanisms underlying brain development and plasticity in health and disease.

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Section: Cccs Control Ionic Plasticitymentioning

confidence: 99%

Section: Cccs Control Ionic Plasticitymentioning

confidence: 99%

Cation-chloride cotransporters in neuronal development, plasticity and disease

et al. 2014

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“…Novija istraživanja na miševima upućuju na važnu ulogu karboanhidraze VII (CAVII) [17]. Ovaj izoenzim je uglavnom eksprimiran u mozgu, a kodiran CAVII genom, koji se u humanom genomu nalazi na dugom kraku hromozoma 16, u regionu 16q21-23 [18].…”

Section: Uvodunclassified

“…Prema Ruusuvuori i sar. [17] ova izoforma povećava bikarbonatima izazvanu GABA-ergičku ekscitaciju tokom intenzivne aktivacije GABAA receptora. Smatra se da učestvuje u modulaciji sinaptičke transmisije u brojnim strukturama CNS-a koje uključuju korteks, hipokampus i bazalne ganglije, gde dovodi do hiperekscitabilnosti, što je polazna pretpostavka o njegovoj ulozi u nastanku Grafikon 1.…”

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Analiza polimorfizma RS185042 u genu za karboanhidrazu VII kod dece sa idiopatskim febrilnim konvulzijama

Cosic¹,

Stojković²,

Svetel³

2014

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SažetakZaključak: Dobijeni rezultati ukazuju na stati stički značajnu razliku u distribuciji alela na lokusu rs185042 CAVII gena između dece obolele od FK i kon trolne grupe, ali se samo na osno vu toga ne može pou zdano tvrditi da je sam gen od ključnog značaja u eti ologiji febrilnih konvulzija.Uvod: Febrilne konvulzije (FK) su najčešće kon vulzije dečjeg doba. Javljaju se sa učestalošću od 25%. Uočeno je da se u nekim porodicama FK javljaju češće, što je ukazalo na genetsku predispoziciju. U poslednje vreme se sve više ispituju različiti enzimi, čija katalitička aktivnost utiče na dinamiku pH i posledično na ekscit abilnost neurona, među kojima je i enzim karboanhi draza VII (CAVII). Alkalna sredina indukuje poveća nje ekscitabilnosti koja je često dovoljno intenzivna za pokretanje epileptiformnih aktivnosti.Cilj: Cilj ovog rada bio je da se ispita da li postoji razlika u učestalosti genotipa na lokusu rs185042 CAVII gena između dece obolele od FK i kontrolne grupe.Materijal i metode: U ovo istraživanje uključeno je 32 dece sa dijagnostikovanim febrilnim konvulzijama i 226 zdrave dece koja su činila kontrolnu grupu. CAVII polimorfizam rs185042 analiziran je metodom PCR/ RFLPs (polymerase chain reaction/restriction fragments length polymorphism).Rezultati: Utvrđeno je da postoji statistički značajna razlika u učestalosti genotipova i alela na lokusu rs185042 gena CAVII između dece sa FK i zdravih kon trola.Ključne reči: Febrilne konvulzije, CAVII gen, po limorfizam rs185042. Abstract Conclusion:The results indicate statistically sig nificant difference in the distribution of alleles at the lo cus rs185042 of the CAVII gene between children with febrile seizures and control group, however, based on this indication only, it cannot be reliably confirmed that CAVII gene alone is a key determinant in the develop ment of febrile seizures.

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In Vivo Evaluation of Selective Carbonic Anhydrase Inhibitors as Potential Anticonvulsant Agents

et al. 2016

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Epilepsy is a common neurological disorder caused by an imbalance between inhibitory and excitatory neurotransmission. It is well known that neuronal excitability is related to γ-aminobutyric acid (GABA)ergic depolarization. HCO3 (-) -dependent depolarization can be suppressed by membrane-permeable inhibitors of carbonic anhydrase. We previously identified some isoquinoline sulfonamides as potent and selective inhibitors of the human carbonic anhydrase II and VII (hCA II and hCA VII) isoforms. Given that hCA II and hCA VII are specific isoforms involved in GABA-mediated neuronal excitation, we hypothesized that they could represent the biological target for the development of new anticonvulsant agents. Therefore, for selected isoquinoline sulfonamides, we preliminarily tested their ability to prevent audiogenic seizures in DBA/2 mice. All compounds were evaluated after intraperitoneal administration, and some of them proved to protect the mice against convulsions. Among this series of compounds, several derivatives showed combined in vivo efficacy with inhibitory effects toward the targeted carbonic anhydrases (i.e., hCA II and hCA VII). Specifically, the most interesting molecule was 1-(4-aminophenyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamide (6), which proved to be a more active and selective hCA VII inhibitor than the reference compound topiramate. Further studies to explore the in vivo pharmacokinetic profile of the most active compounds may help to provide insight into the future design of selective hCA VII inhibitors.

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Neuronal carbonic anhydrase VII provides GABAergic excitatory drive to exacerbate febrile seizures

Cited by 80 publications

References 80 publications

Cation-chloride cotransporters in neuronal development, plasticity and disease

Cation-chloride cotransporters in neuronal development, plasticity and disease

Analiza polimorfizma RS185042 u genu za karboanhidrazu VII kod dece sa idiopatskim febrilnim konvulzijama

In Vivo Evaluation of Selective Carbonic Anhydrase Inhibitors as Potential Anticonvulsant Agents

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