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Mice transgenically overexpressing sulfonylurea receptor 1 in forebrain resist seizure induction and excitotoxic neuron death

AuthorsHernández-Sánchez, Catalina ; Basile, Anthony S.; Fedorova, Irina; Arima, Hiroshi; Stannard, Bethel; Fernández, Ana María; Ito, Yutaka; LeRoith, Derek
Issue Date13-Mar-2001
PublisherNational Academy of Sciences (U.S.)
CitationProceedings of the National Academy of Sciences, 98 (6) : 3549-3554 (2001)
AbstractThe ability of the sulfonylurea receptor (SUR) 1 to suppress seizures and excitotoxic neuron damage was assessed in mice transgenically overexpressing this receptor. Fertilized eggs from FVB mice were injected with a construct containing SUR cDNA and a calcium-calmodulin kinase IIα promoter. The resulting mice showed normal gross anatomy, brain morphology and histology, and locomotor and cognitive behavior. However, they overexpressed the SUR1 transgene, yielding a 9- to 12-fold increase in the density of [3H]glibenclamide binding to the cortex, hippocampus, and striatum. These mice resisted kainic acid-induced seizures, showing a 36% decrease in average maximum seizure intensity and a 75% survival rate at a dose that killed 53% of the wild-type mice. Kainic acid-treated transgenic mice showed no significant loss of hippocampal pyramidal neurons or expression of heat shock protein 70, whereas wild-type mice lost 68–79% of pyramidal neurons in the CA1–3 subfields and expressed high levels of heat shock protein 70 after kainate administration. These results indicate that the transgenic overexpression of SUR1 alone in forebrain structures significantly protects mice from seizures and neuronal damage without interfering with locomotor or cognitive function. ATP-sensitive potassium (KATP) channels are found in cardiac muscle (1) and other excitable cells, including pancreatic β cells, pituicytes, and skeletal and smooth muscle (2). Subcloning and characterization of the molecular components of the KATP channels reveals that they consist of an inwardly rectifying K+ channel (Kir 6.1 or Kir 6.2) (3, 4), which is the pore forming subunit with intrinsic sensitivity to ATP, and a sulfonylurea receptor (SUR) subunit (SUR1, SUR2A/B), which enhances Kir sensitivity to ATP and is itself sensitive to MgADP (5–7). Both subunits associate in a 4:4 stoichiometry to form a functional channel (8). Coexpression studies with SUR and Kir6.x isoforms in heterologous systems result in recombinant KATP channels with different pharmacological and electrophysiological profiles (9–11). Moreover, the complexity of the KATP channel family is increasing with the characterization of new splice variants (12).
The presence of the KATP channels in hippocampus, substantia nigra, striatum, and hypothalamus was indicated by pharmacological and electrophysiological studies (13–16). As in peripheral tissues, KATP channel function is regulated by the ratio of intracellular ATP and ADP concentrations. These channels open to hyperpolarize neurons in response to a decrease in the ratio of ATP/ADP concentrations, thereby linking the membrane potential of neurons to their metabolic status (2). Recently, overlapping expression of SUR and Kir6.x isoforms were found throughout the brain (17, 18), particularly in the hippocampus, where high levels of SUR1, Kir6.2, and Kir6.1 expression are found (17, 18). Although KATP channels may help regulate seizure thresholds (19, 20) and sensitivity to metabolic stress of neurons in the hippocampus and other brain regions (21–23), this concept remains controversial (13, 16). While some investigations suggest that the neuroprotective actions of SUR openers in the hippocampus in vitro may not be mediated by KATP channels (24, 25), single-cell reverse transcriptase–PCR studies indicate that the heterogeneous KATP channel subunit composition in hippocampal neuron subpopulations may explain their differential sensitivity to hypoxia and excitotoxicity (26). Moreover, the inability of SUR openers to penetrate the blood-brain barrier (22) in pharmacologically relevant concentrations prevents studies of the neuroprotective and anticonvulsant properties of these agents from being performed in vivo. To gain further insight into the neuroprotective role of KATP channels in the brain, transgenic (Tg) mice overexpressing the SUR1 subunit in specific forebrain regions were generated by using the calciumcalmodulin kinase II α-subunit (CMK) promoter (27). We now report that the sensitivity of hippocampal pyramidal neurons to kainic acid (KA)-induced hyperexcitability and excitotoxicity was significantly suppressed in Tg mouse lines overexpressing the SUR1 subunit
Description6 páginas, 5 figuras, 3 tablas -- PAGS nros. 3549-3554
Publisher version (URL)http:dx.doi.org/10.1073/pnas.051012898
Appears in Collections:(CIB) Artículos
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