Kindling induces a long-term enhancement in the density of N-type calcium channels in the rat hippocampus

Bernstein, Geula M.; Mendonça, Antonio; Wadia, Jehangir S.; Burnham, W.M.; Jones, Owen

doi:10.1016/s0306-4522(99)00371-1

Cited by 20 publications

(10 citation statements)

References 58 publications

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“…Statistical analysis was carried out by Student's t-test or ANOVA (one-way with Student-Newman-Keuls (SNK) post hoc correction), as appropriate, using 95% confidence limits (SigmaStat software, Jandel Scientific). Contour mapping was performed using Origin V.8 (OriginLab Corp., MA) on images converted from TIFF format to 2D matrices using the TIFFDump algorithm written by J.S Wadia [72]. Particle analysis was performed on thresholded images using NIH Image J.…”

Section: Methodsmentioning

confidence: 99%

Targeting of Voltage-Gated Calcium Channel α2δ-1 Subunit to Lipid Rafts Is Independent from a GPI-Anchoring Motif

et al. 2011

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Voltage-gated calcium channels (Cav) exist as heteromultimers comprising a pore-forming α1 with accessory β and α2δ subunits which modify channel trafficking and function. We previously showed that α2δ-1 (and likely the other mammalian α2δ isoforms - α2δ-2, 3 and 4) is required for targeting Cavs to lipid rafts, although the mechanism remains unclear. Whilst originally understood to have a classical type I transmembrane (TM) topology, recent evidence suggests the α2δ subunit contains a glycosylphosphatidylinositol (GPI)-anchor that mediates its association with lipid rafts. To test this notion, we have used a strategy based on the expression of chimera, where the reported GPI-anchoring sequences in the gabapentinoid-sensitive α2δ-1 subunit have been substituted with those of a functionally inert Type I TM-spanning protein – PIN-G. Using imaging, electrophysiology and biochemistry, we find that lipid raft association of PIN-α2δ is unaffected by substitution of the GPI motif with the TM domain of PIN-G. Moreover, the presence of the GPI motif alone is not sufficient for raft localisation, suggesting that upstream residues are required. GPI-anchoring is susceptible to phosphatidylinositol-phospholipase C (PI-PLC) cleavage. However, whilst raft localisation of PIN-α2δ is disrupted by PI-PLC treatment, this is assay-dependent and non-specific effects of PI-PLC are observed on the distribution of the endogenous raft marker, caveolin, but not flotillin. Taken together, these data are most consistent with a model where α2δ-1 retains its type I transmembrane topology and its targeting to lipid rafts is governed by sequences upstream of the putative GPI anchor, that promote protein-protein, rather than lipid-lipid interactions.

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Section: Methodsmentioning

confidence: 99%

Targeting of Voltage-Gated Calcium Channel α2δ-1 Subunit to Lipid Rafts Is Independent from a GPI-Anchoring Motif

et al. 2011

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“…Genetically modified mice expressing a Q/R unedited GluR‐B subunit to enhance glutamate‐induced calcium influx through AMPA receptors suffer from TLE similar to mice lacking the presynaptic vesicular molecules SV2A and SV2B . This is in line with an increased calcium influx into epileptic neurons , leading to the activation of downstream cellular processes responsible for axonal outgrowth and synaptogenesis. SV2A ligands effectively block seizure activity .…”

Section: Complementary Ion Channel and Neurotransmitter Dynamics In Ementioning

confidence: 99%

Review: Animal models of acquired epilepsy: insights into mechanisms of human epileptogenesis

Becker

2018

Neuropathology Appl Neurobio

130

117

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A. J. Becker (2018) Neuropathology and Applied Neurobiology 44, 112-129 Animal models of acquired epilepsy: insights into mechanisms of human epileptogenesisIn many patients who suffer from epilepsies, recurrent epileptic seizures do not start at birth but develop later in life. This holds particularly true for epilepsies with a focal seizure origin including focal cortical dysplasias and temporal lobe epilepsy (TLE). TLE most frequently has its seizure onset in the hippocampal formation. Hippocampal biopsies of pharmacoresistant TLE patients undergoing epilepsy surgery for seizure control most frequently reveal the damage pattern of hippocampal sclerosis, that is, segmental neuronal cell loss and concomitant astrogliosis. Many TLE patients report on transient brain insults early in life, which is followed by a 'latency' period lacking seizure activity of months or even years before chronic recurrent seizures start. The plethora of structural and cellular mechanisms that convert the hippocampal formation to become chronically hyperexcitable after a transient insult to the brain are summarized under the term epileptogenesis. In contrast to the obstacles arising for experimental studies of epileptogenesis aspects in human surgical hippocampal tissue, recent animal model approaches allow insights into mechanisms of epileptogenesis. Relevant models of transient brain insults in this context comprise several distinct types of lesions including excitoxic status epilepticus (SE), electrical seizure induction, traumatic brain injury, induction of inflammatory processes by hyperthermia and viral inflammation and others. In pathogenetic terms, aberrant transcriptional and epigenetic reprogramming, acquired channel-and synaptopathies, neuronal network and blood-brain barrier dysfunction as well as innate and adaptive immunitymediated damage play major roles. In subsequent steps, respective animal models have been used in order to test whether this dynamic process can be either retarded or even abolished by interfering with epileptogenic mechanisms. Well-controlled subsequent analyses of epileptogenic cascades characterized in animal models using carefully stratified human hippocampal biopsies to exploit the unique opportunities given by these rare and precious brain tissue samples aim to translate into novel antiepileptogenic approaches. Respective preclinical tests can open entirely new perspectives for tailor-made treatments in patients with the potential to avoid the emergence of chronic focal seizure events.

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“…These data suggest that other factors such as altered trafficking may contribute to the enhanced current density of N-type Ca 2+ channels in IC neurons of SN-GEPR-3s. Interestingly, enhanced cell surface density of N-type Ca 2+ channel was reported in the hippocampus following kindling epileptogenesis (Bernstein et al, 1999). Such changes may also occur in IC neurons of SN-GEPR-3s.…”

Section: Discussionmentioning

confidence: 99%

Seizure susceptibility is associated with altered protein expression of voltage-gated calcium channel subunits in inferior colliculus neurons of the genetically epilepsy-prone rat

2010

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The inferior colliculus (IC) is the consensus site for seizure initiation in the genetically epilepsyprone rat (GEPR). We have previously reported that the current density of high threshold voltageactivated (HVA) calcium (Ca 2+ ) channels was markedly enhanced in IC neurons of the GEPR-3 (moderate seizure severity substrain of the GEPR). The present study examines whether subunit protein levels of HVA Ca 2+ channels are altered in IC neurons that exhibit enhanced Ca 2+ current density. Quantification shows that the levels of protein expression of the Ca 2+ channel pore-forming α1D (L-type) and α1E subunits (R-type), were significantly increased in IC neurons of seizure-naive GEPR-3s (SN-GEPR-3s) compared to control Sprague-Dawley (SD) rats. Significant increases and decreases in the levels of protein expression of Ca 2+ channel regulatory β3 and α2δ subunits occurred in IC neurons of SN-GEPR-3s compared to control SD rats, respectively. No changes occurred in the protein expression of Ca 2+ channel pore-forming α1A (P/Q-type), α1B (N-type) and α1C (Ltype) subunits in IC neurons of SN-GEPR-3s compared to control SD rats. A single seizure selectively enhanced protein expression of Ca 2+ channel α1A subunits in IC neurons of GEPR-3s. Thus, upregulation of Ca 2+ channel α1D and α1E subunits may represent the molecular mechanisms for the enhanced current density of L-and R-type of HVA Ca 2+ channels in IC neurons of the GEPR, and may contribute to the genetic basis of their enhanced seizure susceptibility. The up-regulation of Ca 2+ channel α1A subunits induced by seizures may contribute to the increasing IC neuronal excitability that results from repetitive seizures in the GEPR.

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Kindling induces a long-term enhancement in the density of N-type calcium channels in the rat hippocampus

Cited by 20 publications

References 58 publications

Targeting of Voltage-Gated Calcium Channel α2δ-1 Subunit to Lipid Rafts Is Independent from a GPI-Anchoring Motif

Targeting of Voltage-Gated Calcium Channel α2δ-1 Subunit to Lipid Rafts Is Independent from a GPI-Anchoring Motif

Review: Animal models of acquired epilepsy: insights into mechanisms of human epileptogenesis

Seizure susceptibility is associated with altered protein expression of voltage-gated calcium channel subunits in inferior colliculus neurons of the genetically epilepsy-prone rat

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