Glutamate Ionotropic Receptor Kainate Type Subunit 3 (GRIK3) is an important excitatory neurotransmitter receptor that plays a significant role in various neurodegenerative diseases. However, the ...biological functions of GRIK3 in malignancies are largely unknown because of limited related studies. Here, we primarily reported that the expression of GRIK3 was higher in breast cancer tissues than in adjacent noncancerous tissues. GRIK3 expression was also positively correlated with the prognosis of patients with breast cancer. GRIK3 promoted the proliferation and migration abilities of breast cancer cells and enhanced the growth of orthotopically implanted tumors. Mechanically, GRIK3 influenced a range of signaling pathways and key signal transducers, including two epithelial‐mesenchymal transition regulators, SPDEF and CDH1. Heterogenous expression of SPDEF and CDH1 counteracted the migration and invasion abilities, respectively, of breast cancer cells induced by GRIK3. Moreover, overexpression of GRIK3 increased the expression of mesenchymal markers and decreased the expression of epithelial markers, resulting in the translocation of β‐catenin into the nucleus and the increased β‐catenin transcriptional activity. In conclusion, the present study reported a novel oncogenic role of GRIK3. Meanwhile, GRIK3, as a membrane receptor, may also serve as a potential therapeutic target for the treatment of breast cancer.
The aim of this study was to determine the effect of prolactin (PRL) on intracellular calcium (Ca
) concentration and its neuroprotective role in a model of kainic acid (KA) excitotoxicity in primary ...cultures of hippocampal neurons. Cell viability and intracellular Ca
concentrations were determined by MTT and Fura-2 assays, respectively, either after induction by KA as an agonist or after treatment with NBQX antagonist alone or in combination with PRL administration. Expression of ionotropic glutamatergic receptors (iGluRs) subunits in neuronal cells was determined by RT-qPCR. Dose-response treatments with KA or glutamate (Glu), the latter used as endogenous agonist control, induced a significant increase in neuronal intracellular Ca
concentration followed by a significant decrease in hippocampal neuronal viability. Administration of PRL induced a significant increase in neuronal viability after treatment with KA. Furthermore, administration of PRL decreased intracellular Ca
concentrations induced by KA treatment. Independent administration of the AMPAR-KAR antagonist reversed cell death and reduced intracellular Ca
concentration in a similar manner as PRL. Additionally, mRNA expression of AMPAR, KAR and NMDAR subtypes were detected in hippocampal neurons; however, no significant changes in iGluRs subunit expression were observed due to excitotoxicity or PRL treatment. The results suggest that PRL inhibits the increase in intracellular Ca
concentration induced by KA, leading to neuroprotection.
Cognitive impairment is a major concern in temporal lobe epilepsy (TLE). While different experimental models have been used to characterize TLE-related cognitive deficits, little is known on whether ...a particular deficit is more associated with the underlying brain injuries than with the epileptic condition per se. Here, we look at the relationship between the pattern of brain damage and spatial memory deficits in two chronic models of TLE (lithium-pilocarpine, LIP and kainic acid, KA) from two different rat strains (Wistar and Sprague-Dawley) using the Morris water maze and the elevated plus maze in combination with MRI imaging and post-morten neuronal immunostaining. We found fundamental differences between LIP- and KA-treated epileptic rats regarding spatial memory deficits and anxiety. LIP-treated animals from both strains showed significant impairment in the acquisition and retention of spatial memory, and were unable to learn a cued version of the task. In contrast, KA-treated rats were differently affected. Sprague-Dawley KA-treated rats learned less efficiently than Wistar KA-treated animals, which performed similar to control rats in the acquisition and in a probe trial testing for spatial memory. Different anxiety levels and the extension of brain lesions affecting the hippocampus and the amydgala concur with spatial memory deficits observed in epileptic rats. Hence, our results suggest that hippocampal-dependent spatial memory is not necessarily affected in TLE and that comorbidity between spatial deficits and anxiety is more related with the underlying brain lesions than with the epileptic condition per se.
The diatom genus Pseudo-nitzschia (Peragallo) associated with the production of domoic acid (DA), the toxin reposnsible for amnesic shellfish poisoning, is abundant in Scottish waters. A two year ...study examined the relationship between Pseudo-nitzschia cells in the water column and DA concentration in blue mussels (Mytilus edulis) at two sites, and king scallops (Pecten maximus) at one site. The rate of DA uptake and depuration differed greatly between the two species with M. edulis whole tissue accumulating and depurating 7μgg−1 (now expressed as mgkg−1) per week. In contrast, it took 12 weeks for DA to depurate from P. maximus gonad tissue from a concentration of 68μgg−1 (now mgkg−1) to <20μgg−1 (now mgkg‐1). The DA depuration rate from P. maximus whole tissue was <5% per week during both years of the study. Correlations between the Pseudo-nitzschia cell densities and toxin concentrations were weak to moderate for M. edulis and weak for P. maximus. Seasonal diversity on a species level was observed within the Pseudo-nitzschia genus at both sites with more DA toxicity associated with summer/autumn Pseudo-nitzschia blooms when P. australis was observed in phytoplankton samples. This study reveals the marked difference in DA uptake and depuration in two shellfish species of commercial importance in Scotland. The use of these shellfish species to act as a proxy for DA in the environment still requires investigation.
•Kainate receptors (KARs) can signal through canonical and non-canonical pathways.•KARs regulate neurotransmitter release and synaptic plasticity in different synapses.•KARs can modulate synaptic ...plasticity depending on the activity level of the synapse.
Extensive research over the past decades has characterized multiple forms of synaptic plasticity, identifying them as key processes that allow the brain to operate in a dynamic manner. Within the wide variety of synaptic plasticity modulators, kainate receptors are receiving increasing attention, given their diversity of signaling mechanisms and cellular expression profile. Here, we summarize the experimental evidence about the involvement of kainate receptor signaling in the regulation of short- and long-term plasticity, from the perspective of the regulation of neurotransmitter release. In light of this evidence, we propose that kainate receptors may be considered homeostatic modulators of neurotransmitter release, able to bidirectionally regulate plasticity depending on the functional history of the synapse.
Excitotoxicity is considered to be an important mechanism involved in various neurodegenerative diseases in the central nervous system (CNS) such as Alzheimer's disease (AD). However, the mechanism ...by which excitotoxicity is implicated in neurodegenerative disorders remains unclear. Kainic acid (KA) is an epileptogenic and neuroexcitotoxic agent by acting on specific kainate receptors (KARs) in the CNS. KA has been extensively used as a specific agonist for ionotrophic glutamate receptors (iGluRs), for example, KARs, to mimic glutamate excitotoxicity in neurodegenerative models as well as to distinguish other iGluRs such as α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors and N-methyl-D-aspartate receptors. Given the current knowledge of excitotoxicity in neurodegeneration, interventions targeted at modulating excitotoxicity are promising in terms of dealing with neurodegenerative disorders. This paper summarizes the up-to-date knowledge of neurodegenerative studies based on KA-induced animal model, with emphasis on its potentials and limitations.
Alterations of the enteric glutamatergic transmission may underlay changes in the function of myenteric neurons following intestinal ischemia and reperfusion (I/R) contributing to impairment of ...gastrointestinal motility occurring in these pathological conditions. The aim of the present study was to evaluate whether glutamate receptors of the NMDA and AMPA/kainate type are involved in myenteric neuron cell damage induced by I/R. Primary cultured rat myenteric ganglia were exposed to sodium azide and glucose deprivation (in vitro chemical ischemia). After 6 days of culture, immunoreactivity for NMDA, AMPA and kainate receptors subunits, GluN(1) and GluA(1-3), GluK(1-3) respectively, was found in myenteric neurons. In myenteric cultured ganglia, in normal metabolic conditions, -AP5, an NMDA antagonist, decreased myenteric neuron number and viability, determined by calcein AM/ethidium homodimer-1 assay, and increased reactive oxygen species (ROS) levels, measured with hydroxyphenyl fluorescein. CNQX, an AMPA/kainate antagonist exerted an opposite action on the same parameters. The total number and viability of myenteric neurons significantly decreased after I/R. In these conditions, the number of neurons staining for GluN1 and GluA(1-3) subunits remained unchanged, while, the number of GluK(1-3)-immunopositive neurons increased. After I/R, -AP5 and CNQX, concentration-dependently increased myenteric neuron number and significantly increased the number of living neurons. Both -AP5 and CNQX (100-500 µM) decreased I/R-induced increase of ROS levels in myenteric ganglia. On the whole, the present data provide evidence that, under normal metabolic conditions, the enteric glutamatergic system exerts a dualistic effect on cultured myenteric ganglia, either by improving or reducing neuron survival via NMDA or AMPA/kainate receptor activation, respectively. However, blockade of both receptor pathways may exert a protective role on myenteric neurons following and I/R damage. The neuroprotective effect may depend, at least in part, on the ability of both receptors to increase intraneuronal ROS production.
Alternative splicing in the extracellular ligand binding domain of the AMPA receptors generates two variants, i.e., flip and flop. The flop variant of the GluR2 AMPA receptor is known to desensitize ...faster than the flip counterpart, whereas the GluR1 flip and flop variants exhibit the same rate of desensitization. However, whether the alternative splicing affects the channel opening kinetic properties of these receptors is unknown. Using a laser-pulse photolysis technique, we have characterized the channel opening kinetic mechanism for the flip and flop channels of GluR1 and GluR2, respectively. We find that the flop variant of GluR2 opens the channel, following the binding of glutamate, with the same rate as the flip channel, but closes its channel more rapidly. The difference in the kinetic properties between the two receptor isoforms can be described by a model we proposed previously in which the channel closing rate, a measure of the stability of the open channel state, controls an apparent tendency of the channel to desensitize, most likely, through the closed channel state. Specifically, the flop sequence of GluR2 promotes the channel to close more rapidly and consequently to desensitize with a faster rate than the flip sequence. For GluR1, the alternative splicing does not seem to affect the channel opening kinetics, since the flip and flop variants of GluR1 have the same channel opening rate, and the same channel closing rate. As expected and indeed observed, the flop variant desensitizes with the same rate as the flip variant does. On the basis of these results, we hypothesize that the flip/flop sequence cassette of AMPA receptors, in a sequence-dependent manner, regulates the rate of the channel closing process, in the microsecond time domain, through which it further regulates the channel desensitization in the millisecond time region.
Mood disorders are associated with regional brain abnormalities, including reductions in glial cell and neuron number, glutamatergic irregularities, and differential patterns of brain activation. ...Because astrocytes are modulators of neuronal activity and are important in trafficking the excitatory neurotransmitter glutamate, it is possible that these pathologies are interrelated and contribute to some of the behavioral signs that characterize depression and related disorders. We tested this hypothesis by determining whether depressive-like signs were induced by blocking central astrocytic glutamate uptake with the astrocytic glutamate transporter (GLT-1) inhibitor, dihydrokainic acid (DHK), in behavioral tests that quantify aspects of mood, including reward and euthymia/dysthymia: intracranial self-stimulation (ICSS) and place conditioning. We found that DHK elevated ICSS thresholds, a depressive-like effect that could reflect reduced sensitivity to reward (anhedonia) or increased aversion (dysphoria). However, DHK treatment did not establish conditioned place aversions, suggesting that this treatment does not induce dysphoria. To identify the brain regions mediating the behavioral effects of DHK, we examined c-Fos expression in areas implicated in motivation and emotion. DHK increased c-Fos expression in many of these regions. The dentate gyrus of the hippocampus was robustly activated, which led us to explore whether DHK alters hippocampal learning. DHK impaired spatial memory in the MWM. These findings identify disruption of astrocyte glutamate uptake as one component of the complex circuits that mediate anhedonia and cognitive impairment, both of which are common symptoms of depression. These finding may have implications for the etiology of depression and other disorders that share the features of anhedonia and cognitive impairment.
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