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https://www.readbyqxmd.com/read/28496181/the-neuronal-k-cl-co-transporter-2-slc12a5-modulates-insulin-secretion
#1
Shams Kursan, Timothy S McMillen, Pavani Beesetty, Eduardo Dias-Junior, Mohammed M Almutairi, Abu A Sajib, J Ashot Kozak, Lydia Aguilar-Bryan, Mauricio Di Fulvio
Intracellular chloride concentration ([Cl(-)]i) in pancreatic β-cells is kept above electrochemical equilibrium due to the predominant functional presence of Cl(-) loaders such as the Na(+)K(+)2Cl(-) co-transporter 1 (Slc12a2) over Cl(-)extruders of unidentified nature. Using molecular cloning, RT-PCR, Western blotting, immunolocalization and in vitro functional assays, we establish that the "neuron-specific" K(+)Cl(-) co-transporter 2 (KCC2, Slc12a5) is expressed in several endocrine cells of the pancreatic islet, including glucagon secreting α-cells, but particularly in insulin-secreting β-cells, where we provide evidence for its role in the insulin secretory response...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28477354/a-de-novo-missense-mutation-in-slc12a5-found-in-a-compound-heterozygote-patient-with-epilepsy-of-infancy-with-migrating-focal-seizures
#2
T Saito, A Ishii, K Sugai, M Sasaki, S Hirose
Epilepsy of infancy with migrating focal seizures (EIMFS) is an infantile epileptic encephalopathy characterized by refractory seizures, severe psychomotor delay, and multiple moving epileptic discharges. The genetic etiology of EIMFS is relatively homogeneous with the majority of causative mutations found in KCNT1. Currently, gene panel or whole-exome sequencing is used for testing. To verify the pathogenicity of a variant, co-segregation of the variant and the disorder in a pedigree is important; hence, de novo mutations that are judged to be deleterious may be considered pathogenic because the patients are isolated...
May 6, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28451854/role-of-vasopressin-in-rat-models-of-salt-dependent-hypertension
#3
REVIEW
Masha Prager-Khoutorsky, Katrina Y Choe, David I Levi, Charles W Bourque
PURPOSE OF REVIEW: Dietary salt intake increases both plasma sodium and osmolality and therefore increases vasopressin (VP) release from the neurohypophysis. Although this effect could increase blood pressure by inducing fluid reabsorption and vasoconstriction, acute activation of arterial baroreceptors inhibits VP neurons via GABAA receptors to oppose high blood pressure. Here we review recent findings demonstrating that this protective mechanism fails during chronic high salt intake in rats...
May 2017: Current Hypertension Reports
https://www.readbyqxmd.com/read/28450542/neuronal-chloride-regulation-via-kcc2-is-modulated-through-a-gabab-receptor-protein-complex
#4
Rebecca Wright, Sarah E Newey, Andrei Ilie, Winnie Wefelmeyer, Joseph V Raimondo, Rachel Ginham, R A Jeffrey Mcllhinney, Colin J Akerman
GABAB receptors are G-protein coupled receptors that mediate inhibitory synaptic actions through a series of downstream target proteins. It is increasingly appreciated that the GABAB receptor forms part of larger signalling complexes, which enable the receptor to mediate multiple different effects within neurons. Here we report that GABAB receptors can physically associate with the potassium-chloride cotransporter protein, KCC2, which sets the driving force for the chloride permeable ionotropic GABAA receptor in mature neurons...
April 27, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28433802/role-of-environmental-stressors-in-determining-the-developmental-outcome-of-neonatal-anesthesia
#5
Ling-Sha Ju, Jiao-Jiao Yang, Nikolaus Gravenstein, Christoph N Seubert, Timothy E Morey, Colin Sumners, Terrie Vasilopoulos, Jian-Jun Yang, Anatoly E Martynyuk
BACKGROUND: The majority of studies evaluating neurocognition in humans who had procedures under anesthesia early in life found long-term deficits even though the typical anesthesia duration normalized to the human life span is much shorter than that shown to induce developmental abnormalities in rodents. Therefore, we studied whether subsequent environmental stressors contribute to deficiencies programmed by a brief neonatal etomidate exposure. METHODS: Postnatal days (P) 4, 5, or 6, Sprague-Dawley rats, pretreated with vehicle or the Na(+)-K(+)-2Cl(-) (NKCC1) inhibitor, bumetanide, received two injections of etomidate resulting in anesthesia for 2h...
April 7, 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/28426550/neuropathic-pain-after-chronic-nerve-constriction-may-not-correlate-with-chloride-dysregulation-in-mouse-trigeminal-nucleus-caudalis-neurons
#6
Alberto Castro, Ying Li, Charles Raver, Ramesh Chandra, Radi Masri, Mary Kay Lobo, Asaf Keller
Changes in chloride reversal potential in rat spinal cord neurons have previously been associated with persistent pain in nerve injury and inflammation models. These changes correlate with a decrease in the expression of the potassium% chloride transporter, KCC2, and with increases in neuronal excitability. Here, we test the hypothesis that similar changes occur in mice with neuropathic pain induced by chronic constriction injury of the trigeminal infraorbital nerve (CCI¬-ION). This model allows us to distinguish an acute pain phase (3-¬5 days after injury) from a persistent pain phase (12¬-14 days after CCI-¬ION)...
April 18, 2017: Pain
https://www.readbyqxmd.com/read/28425312/activation-of-spinal-alpha-7-nicotinic-acetylcholine-receptor-shortens-the-duration-of-remifentanil-induced-postoperative-hyperalgesia-by-upregulating-kcc2-in-the-spinal-dorsal-horn-in-rats
#7
Wei Gu, Wei Zhang, Yishan Lei, Yin Cui, Shuaishuai Chu, Xiaoping Gu, Zhengliang Ma
Background Accumulating evidence has shown that the signal from spinal brain-derived neurotrophic factor/tyrosine receptor kinase B-K(+)-Cl(-) cotransporter-2 plays a critical role in the process of pain hypersensitivity. The activation of alpha-7 nicotinic acetylcholine receptors could have an analgesic effect on remifentanil-induced postoperative hyperalgesia. Nevertheless, whether intrathecal administration of PNU-120596, an alpha-7 nicotinic acetylcholine receptors selective type II positive allosteric modulator, before surgery could affect the duration of remifentanil-induced postoperative hyperalgesia remains unknown, and the effects of alpha-7 nicotinic acetylcholine receptors activation on the brain-derived neurotrophic factor/tyrosine receptor kinase B-K(+)-Cl(-) cotransporter-2 signal in the spinal dorsal horn of rats with remifentanil-induced postoperative hyperalgesia is still enigmatic...
January 2017: Molecular Pain
https://www.readbyqxmd.com/read/28394853/targeting-brain-derived-neurotrophic-factor-in-the-medial-thalamus-for-the-treatment-of-central-poststroke-pain-in-a-rodent-model
#8
Hsi-Chien Shih, Yung-Hui Kuan, Bai-Chung Shyu
Approximately 7% to 10% of patients develop a chronic pain syndrome after stroke. This chronic pain condition is called central poststroke pain (CPSP). Recent studies have observed an abnormal increase in the secretion of brain-derived neurotrophic factor (BDNF) in spinal cord tissue after spinal cord injury. An animal model of CPSP was established by an intrathalamus injection of collagenase. Mechanical and thermal allodynia was induced after lesions of the thalamic ventral basal complex in rats. Four weeks after the injection, the number of neurons decreased, the number of astrocytes, microglia, and P2X4 receptors increased, and BDNF mRNA expression increased in the brain lesion area...
May 10, 2017: Pain
https://www.readbyqxmd.com/read/28374007/contribution-of-resting-conductance-gabaa-receptor-mediated-miniature-synaptic-currents-and-neurosteroid-to-chloride-homeostasis-in-central-neurons
#9
Tushar D Yelhekar, Michael Druzin, Staffan Johansson
Maintenance of a low intraneuronal Cl(-) concentration, [Cl(-)]i, is critical for inhibition in the CNS. Here, the contribution of passive, conductive Cl(-) flux to recovery of [Cl(-)]i after a high load was analyzed in mature central neurons from rat. A novel method for quantifying the resting Cl(-) conductance, important for [Cl(-)]i recovery, was developed and the possible contribution of GABAA and glycine receptors and of ClC-2 channels to this conductance was analyzed. The hypothesis that spontaneous, action potential-independent release of GABA is important for [Cl(-)]i recovery was tested...
March 2017: ENeuro
https://www.readbyqxmd.com/read/28344592/dysbindin-deficiency-modifies-the-expression-of-gaba-neuron-and-ion-permeation-transcripts-in-the-developing-hippocampus
#10
Jennifer Larimore, Stephanie A Zlatic, Miranda Arnold, Kaela S Singleton, Rebecca Cross, Hannah Rudolph, Martha V Bruegge, Andrea Sweetman, Cecilia Garza, Eli Whisnant, Victor Faundez
The neurodevelopmental factor dysbindin is required for synapse function and GABA interneuron development. Dysbindin protein levels are reduced in the hippocampus of schizophrenia patients. Mouse dysbindin genetic defects and other mouse models of neurodevelopmental disorders share defective GABAergic neurotransmission and, in several instances, a loss of parvalbumin-positive interneuron phenotypes. This suggests that mechanisms downstream of dysbindin deficiency, such as those affecting GABA interneurons, could inform pathways contributing to or ameliorating diverse neurodevelopmental disorders...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28337033/cortical-cells-reveal-app-as-a-new-player-in-the-regulation-of-gabaergic-neurotransmission
#11
Anna Doshina, Florian Gourgue, Michiho Onizuka, Remi Opsomer, Peng Wang, Kunie Ando, Bernadette Tasiaux, Ilse Dewachter, Pascal Kienlen-Campard, Jean-Pierre Brion, Philippe Gailly, Jean-Noël Octave, Nathalie Pierrot
The amyloid precursor protein (APP) modulates synaptic activity, resulting from the fine tuning of excitatory and inhibitory neurotransmission. GABAergic inhibitory neurotransmission is affected by modifications in intracellular chloride concentrations regulated by Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) and neuronal K(+)-Cl(-) cotransporter 2 (KCC2), allowing entrance and efflux of chloride, respectively. Modifications in NKCC1 and KCC2 expression during maturation of cortical cells induce a shift in GABAergic signaling...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28336934/low-frequency-stimulation-of-the-primary-focus-retards-positive-transfer-of-secondary-focus
#12
Yifang Kuang, Cenglin Xu, Yinxi Zhang, Yi Wang, Xiaohua Wu, Ying Wang, Yao Liu, Kai Zhong, Hui Cheng, Yi Guo, Shuang Wang, Meiping Ding, Zhong Chen
Positive transfer of secondary focus (PTS) refers to new epileptogenesis outside the primary focus and is minimally controlled by existing treatments. Low-frequency stimulation (LFS) has benefits on the onset of epilepsy and epileptogenesis. However, it's unclear whether LFS can retard the PTS in epilepsy. Here we found that PTS at both contralateral amygdala and ipsilateral hippocampus were promoted after the primary focus was fully kindled in rat kindling model. The promotion of PTS at the mirror focus started when the primary kindling acquisition reached focal seizures...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28301408/k-cl-cotransporter-2-mediated-cl-extrusion-determines-developmental-stage-dependent-impact-of-propofol-anesthesia-on-dendritic-spines
#13
Martin Puskarjov, Hubert Fiumelli, Adrian Briner, Timea Bodogan, Kornel Demeter, Claudia-Marvine Lacoh, Martina Mavrovic, Peter Blaesse, Kai Kaila, Laszlo Vutskits
BACKGROUND: General anesthetics potentiating γ-aminobutyric acid (GABA)-mediated signaling are known to induce a persistent decrement in excitatory synapse number in the cerebral cortex when applied during early postnatal development, while an opposite action is produced at later stages. Here, the authors test the hypothesis that the effect of general anesthetics on synaptogenesis depends upon the efficacy of GABA receptor type A (GABAA)-mediated inhibition controlled by the developmental up-regulation of the potassium-chloride (K-Cl) cotransporter 2 (KCC2)...
May 2017: Anesthesiology
https://www.readbyqxmd.com/read/28279020/kcc2-downregulation-facilitates-epileptic-seizures
#14
Lulan Chen, Li Wan, Zheng Wu, Wanting Ren, Yian Huang, Binbin Qian, Yun Wang
GABAA receptor-mediated inhibition depends on the maintenance of low level intracellular [Cl(-)] concentration, which in adult depends on neuron specific K(+)-Cl(-) cotransporter-2 (KCC2). Previous studies have shown that KCC2 was downregulated in both epileptic patients and various epileptic animal models. However, the temporal relationship between KCC2 downregulation and seizure induction is unclear yet. In this study, we explored the temporal relationship and the influence of KCC2 downregulation on seizure induction...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28235805/a-kainate-receptor-subunit-promotes-the-recycling-of-the-neuron-specific-k-cl-co-transporter-kcc2-in-hippocampal-neurons
#15
Jessica C Pressey, Vivek Mahadevan, C Sahara Khademullah, Zahra Dargaei, Jonah Chevrier, Wenqing Ye, Michelle Huang, Alamjeet K Chauhan, Steven J Meas, Pavel Uvarov, Matti S Airaksinen, Melanie A Woodin
Synaptic inhibition depends on a transmembrane gradient of chloride, which is set by the neuron-specific K(+)-Cl(-) co-transporter KCC2. Reduced KCC2 levels in the neuronal membrane contribute to the generation of epilepsy, neuropathic pain, and autism spectrum disorders; thus, it is important to characterize the mechanisms regulating KCC2 expression. In the present study, we determined the role of KCC2-protein interactions in regulating total and surface membrane KCC2 expression. Using quantitative immunofluorescence in cultured mouse hippocampal neurons, we discovered that the kainate receptor subunit GluK2 and the auxiliary subunit Neto2 significantly increase the total KCC2 abundance in neurons but that GluK2 exclusively increases the abundance of KCC2 in the surface membrane...
April 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28223240/carbachol-induced-network-oscillations-in-an-in-vitro-limbic-system-brain-slice
#16
Maxime Lévesque, Mauro Cataldi, Li-Yuan Chen, Shabnam Hamidi, Massimo Avoli
We employed simultaneous field potential recordings from CA3, subiculum and entorhinal cortex in an in vitro brain slice preparation to understand the involvement of these limbic areas in the generation of the field potential oscillations that are induced by bath application of the muscarinic receptor agonist carbachol. Regularly spaced oscillations that mainly presented at theta frequency range (5-12Hz) occurred synchronously in all three structures in the presence of carbachol. These oscillations, which disappeared when slices were perfused with pirenzepine or with glutamatergic receptor antagonists, were categorized as short (<4s) and long (>4s) with short events oscillating at higher frequencies than long events...
February 21, 2017: Neuroscience
https://www.readbyqxmd.com/read/28143398/a-noninvasive-optical-approach-for-assessing-chloride-extrusion-activity-of-the-k-cl-cotransporter-kcc2-in-neuronal-cells
#17
Anastasia Ludwig, Claudio Rivera, Pavel Uvarov
BACKGROUND: Cation-chloride cotransporters (CCCs) are indispensable for maintaining chloride homeostasis in multiple cell types, but K-Cl cotransporter KCC2 is the only CCC member with an exclusively neuronal expression in mammals. KCC2 is critical for rendering fast hyperpolarizing responses of ionotropic γ-aminobutyric acid and glycine receptors in adult neurons, for neuronal migration in the developing central nervous system, and for the formation and maintenance of small dendritic protrusions-dendritic spines...
January 31, 2017: BMC Neuroscience
https://www.readbyqxmd.com/read/28101155/the-5-ht2a-receptor-potassium-chloride-cotransporter-2-signaling-pathway-in-a-rat-incision-pain-model
#18
Rong Dong, Buwei Yu, Lijiao Chen, Weifeng Yu
Postoperative pain is a critical problem in clinical pain administration. Due to the unclear formation mechanism of postoperative pain, the treatment of postoperative pain is still in the symptomatic treatment stage and lacking satisfactory analgesic effect. Postoperative pain can be simulated by using a rat incision pain model. We observed changes in pain-related behavior of rats affected by the 5-hydroxytryptamine 2A receptor (5-HT2AR) agonist, TCB-2, and antagonist, ketanserin, through intrathecal delivery...
December 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28074534/depolarizing-gaba-contributes-to-glutamatergic-network-rewiring-in-epilepsy
#19
Nazim Kourdougli, Christophe Pellegrino, Juho-Matti Renko, Stanislav Khirug, Geneviève Chazal, Tiina-Kaisa Kukko-Lukjanov, Sari E Lauri, Jean-Luc Gaiarsa, Liang Zhou, Angélique Peret, Eero Castrén, Raimo Kalevi Tuominen, Valérie Crépel, Claudio Rivera
OBJECTIVE: Rewiring of excitatory glutamatergic neuronal circuits is a major abnormality in epilepsy. Besides the rewiring of excitatory circuit, an abnormal depolarizing GABAergic drive has been hypothesized to participate in the epileptogenic processes. However, a remaining clinically relevant question is whether early post Status Epilepticus (SE) evoked chloride dysregulation is important for the remodeling of aberrant glutamatergic neuronal circuit. METHODS: Osmotic mini-pumps were used to infuse intracerebrally a specific inhibitor of depolarizing GABAergic transmission as well as a functionally blocking antibody towards the pan-neurotrophin receptor p75 (p75(NTR) )...
January 11, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28057537/the-chloride-co-transporters-nkcc1-and-kcc2-in-experimental-autoimmune-encephalomyelitis-eae
#20
Muhammad Saad Yousuf, Kasia Zubkow, Gustavo Tenorio, Bradley Kerr
Patients with multiple sclerosis (MS) often complain of neuropathic pain. According to the Gate Control Theory of Pain, spinal networks of GABAergic inhibitory interneurons are important in modulating nociceptive inputs from the periphery. Na+-K+-2Cl- co-transporter 1 (NKCC1) and K+-Cl- co-transporter 2 (KCC2) generally dictate the tone of GABA/glycine inhibition by regulating intracellular chloride concentrations. In this study, we investigated the role of NKCC1 and KCC2 in neuropathic pain observed in the animal model, experimental autoimmune encephalomyelitis (EAE), a commonly used model to study the pathophysiology of MS...
March 6, 2017: Neuroscience
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