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Hepatic Cancer
Published in Dongyou Liu, Tumors and Cancers, 2017
Common single-nucleotide polymorphisms (SNPs) consist of rs2880301 (TPTE2), rs17401966 (KIF1B), rs17401966 (KIF1B), rs455804 (GRIK1), rs9272015 (HLA-DQA1/DRB1), rs2596542 (MICA), rs9275319 (HLA-DQ), rs1012068 (DEPDC5), rs2551677 (DDX18), rs763110 (FasL), rs3816747 (DLC1), rs7574865, and rs3761549 (FOXP3).
Animal Models of Down Syndrome and Other Genetic Diseases Associated with Mental Retardation
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Angela J. Villar, Charles J. Epstein
Although individuals with DS are not insensitive to pain, they do express pain or discomfort more slowly and less precisely than the general population (85). Pain research has found that patients with DS exhibit longer pain latencies and are less accurate in their ability to locate cold stimuli. This elevated sensory threshold and a decreased ability to localize stimuli could be due to a combination of factors, including, delayed pain transmission, a delay in the pain integration process and delayed motor response (verbal or pointing). As in DS, Ts65Dn mice also show reduced responsiveness to painful stimuli (86,87). During tonic pain, Martinez-Cue et al. (86) reported that Ts65Dn mice showed less licking in the early and late phase after subcutaneous formalin injection compared with control littermates. Latency in the tail-flick was increased in Ts65Dn animals after cumulative doses of morphine, indicating an increase in a nociceptive threshold. In contrast, Cao et al. (87) found no differences in tail-flick latency and formalin test responses between Ts65Dn and controls. However, the Ts65Dn mice showed significantly increased latency in the hot plate and tail clip tests (87). Interestingly, the magnitude of their response did not differ from controls suggesting that, like DS individuals, Ts65Dn mice are not insensitive to pain sensation. The authors suggest that altered sensitivity to pain reflects either diminished peripheral nociceptor responsiveness and/or decreased central processing of nociceptive signals. Overexpression of Grik1, encoding the GluR5 subunit of the kainate receptor, has been shown to participate in pain transmission (88) and may play a role in reduced pain sensitivity.
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
The ionotropic glutamate receptors are ion channels for sodium, potassium, and calcium similar to the nicotinic ACh receptor. These ligand-gated channels are opened by glutamate as well as various synthetic chemicals with a similar structure leading to excitation (depolarization) of the neuron on which they are found. Three subtypes of ionotropic glutamate receptors have been identified based on the chemicals that were highly effective in activating them: 1) N-methyl-D-aspartate or NMDA receptor, 2) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid or AMPA receptor, and 3) kainic acid or kainate receptor. In the past, these receptors were separated into NMDA and non-NMDA because of the antagonists that blocked either the NMDA or non-NMDA (AMPA, kainate) receptors. Another difference between NMDA and non-NMDA receptors is their selectivity for ion conductance with NMDA channels able to conduct sodium and calcium and non-NMDA (AMPA, kainate) that typically depolarize the cell with a sodium current. Just as the nicotinic ACh and GABA receptors were composed of several protein subunits that form the ion channel, the EAA receptors are also composed of subunits. However, unlike the nicotinic ACh, GABA and glycine receptors, which were composed of five subunits (i.e., pentamers), the ionotropic glutamate receptors are composed of four protein subunits (i.e., tetramers). A variety of protein subunits that comprise the EAA receptors have been identified through molecular cloning. The subunits for the NMDA receptor are referred to as GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, and GluN3B, and those for the AMPA receptor are designated as GluA1–GluA4. The protein subunits that form the kainate receptor include GluK1–GluK5.168 The subunit composition of an NMDA or non-NMDA receptor may differ in different regions of the brain.
On the path toward personalized medicine: implications of pharmacogenetic studies of alcohol use disorder medications
Published in Expert Review of Precision Medicine and Drug Development, 2020
Steven J. Nieto, Erica N. Grodin, Lara A. Ray
Acute alcohol intake inhibits glutamate neurotransmission by reducing glutamate binding at the NMDA receptor. Indeed, glutamatergic dysregulation has been implicated in the allostatic theory of addiction [70]. Both ionotropic and metabotropic receptors mediate the synaptic effects of glutamate. Pharmacogenetic studies have focused on variants in the subunits of glutamate receptors, namely GluK1 (encoded by GRIK1) and GluN2B (encoded by GRIN2B) (see Table 2). Kranzler and colleagues [71] found that genetic variation in GRIK1 (rs2832407) was associated with AUD and that C homozygotes showed fewer drinking days and more days abstinent when treated with topiramate versus placebo, whereas topiramate was not effective over placebo in A carriers. Furthermore, C homozygotes continued to have fewer drinking days relative to A carriers when assessed 3- and 6-months post-treatment [72]. Ray et al. [73] examined three GRIK1 SNPs, including rs2832407, as potential moderators of severity of topiramate side effects. Results from this study showed that C homozygotes had lower adverse side effects and lower topiramate serum levels relative to A carriers.
A kainate receptor GluK4 deletion, protective against bipolar disorder, is associated with enhanced cognitive performance across diagnoses in the TwinsUK cohort
Published in The World Journal of Biological Psychiatry, 2019
Maria Koromina, Miles Flitton, Ian R. Mellor, Helen Miranda Knight
Kainate receptors are ionotropic glutamate receptors involved in cellular functions necessary for learning and memory, such as synaptic plasticity, long-term potentiation and neurotransmission (Bortolotto et al. 1999; Schmitz et al. 2003; Bortolotto et al. 2005; Lerma and Marques 2013; Sihra and Rodriguez-Moreno 2013; Sihra et al. 2014). They are composed of tetrameric combinations of five subunits (GluK1-GluK5; encoded by GRIK1-GRIK5) and modulated by auxiliary proteins Neto1 and Neto2 (Lerma et al. 2001; Jane et al. 2009; Traynelis et al. 2010; Han et al. 2016; Kristensen et al. 2016; Li et al. 2016). We have previously reported GRIK4/GluK4 as a breakpoint gene disrupted in a complex chromosomal rearrangement in a patient diagnosed with schizophrenia co-morbid with learning disability (Pickard et al. 2006, 2008). Subsequent case–control genetic studies led to the identification of a 14-base pair deletion variant (indel) (rs869187535) within the 3′ untranslated region of the gene which was negatively associated with bipolar disorder (Pickard et al. 2006; Knight et al. 2012).
Ionotropic glutamate receptors in platelets: opposing effects and a unifying hypothesis
Published in Platelets, 2021
Maggie L. Kalev-Zylinska, Marie-Christine Morel-Kopp, Christopher M. Ward, James I. Hearn, Justin R. Hamilton, Anna Y. Bogdanova
KAR are structurally and functionally similar to AMPAR [2]. There are five possible KAR subunits (GluK1–GluK5) encoded by GRIK1–GRIK5 genes; only GluK1 and GluK2 are expressed in platelets (Tables I and II) [19]. RNA editing of GRIK transcripts can render KAR Ca2+-impermeable in a similar fashion to editing of GRIA2 (Figure 1A and C). Like AMPAR, KAR respond quickly to glutamate release into the synapse and support mostly influx of Na+; however, KAR current is marginally slower and smaller than AMPAR (Figure 1D). KAR interact with the ancillary proteins including Neto and GRIP1 that stabilize the receptor in the plasma membrane and support signaling downstream (Table I) [2,36].