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GABA receptors

Marwa Y Sallam, Sahar M El-Gowilly, Abdel-Galil A Abdel-Galil, Mahmoud M El-Mas
We have previously shown that cyclosporine (CSA) counteracts cardiovascular manifestations induced by endotoxemia (lipopolysaccharide, LPS) such as hypotension and cardiac autonomic dysfunction in conscious rats. In this study we investigated whether the facilitation of central γ-amino butyric acid (GABA) neurotransmission blunts these favorable influences of CSA. The LPS-CSA interaction was determined in the absence and presence of drugs that activate GABAA or GABAB receptors or elevate synaptic GABA levels in the central nervous system...
April 18, 2018: Fundamental & Clinical Pharmacology
Marta Skelin, Danijel Bursać, Viviana Kozina, Tristan Winters, Marija Macan, Marija Ćurlin
Cervical mucus modulates fertility by cyclical changes of its biophysical and functional properties. Based on an analogy with bronchial goblet cells we set out to investigate the possible role of the gamma-aminobutyric acid (GABA) signalling pathway in the mediation of oestrogen-induced mucus secretion from endocervical secretory cells. The aim of the study was to examine the existence of GABAA receptor (GABAAR), glutamic acid decarboxylase 65/67 (GAD65/67) and vesicular GABA transporter (VGAT) in human and mouse cervical tissue...
April 18, 2018: Reproduction, Fertility, and Development
Mehdi Farokhnia, Mikela B Sheskier, Mary R Lee, April N Le, Erick Singley, Sofia Bouhlal, Timmy Ton, Zhen Zhao, Lorenzo Leggio
Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system, plays an important role in biobehavioral processes that regulate alcohol seeking, food intake, and stress response. The metabotropic GABA-B receptor has been investigated as a potential therapeutic target for alcohol use disorder, by using orthosteric agonists (e.g., baclofen) and positive allosteric modulators. Whether and how pharmacological manipulation of the GABA-B receptor, in combination with alcohol intake, may affect feeding- and stress-related neuroendocrine pathways remains unknown...
April 14, 2018: Neuropharmacology
Dhani Biscocho, Jayce G Cook, Joshua Long, Nishant Shah, Esther M Leise
The marine mud snail, Tritia (=Ilyanassa) obsoleta, displays a biphasic life cycle. During the initial phase of early development, embryos hatch from benthic egg capsules to become weakly swimming veliger larvae. In the second phase, adult T. obsoleta are facultative carnivores and major agents of community disturbance. Metamorphosis is the irreversible developmental event that links these two life history stages. When physiologically competent, larvae can respond to appropriate environmental cues by settling onto their mudflat habitat and transforming themselves into miniature adult snails...
April 16, 2018: Developmental Neurobiology
Munia F Sowaileh, Amy E Salyer, Kuldeep K Roy, Jinu P John, James R Woods, Robert J Doerksen, Gregory H Hockerman, David A Colby
β-Hydroxy difluoromethyl ketones represent the newest class of agonists of the GABA-B receptor, and they are structurally distinct from all other known agonists at this receptor because they do not display the carboxylic acid or amino group of γ-aminobutyric acid (GABA). In this report, the design, synthesis, and biological evaluation of additional analogues of β-hydroxy difluoromethyl ketones characterized the critical nature of the substituted aromatic group on the lead compound. The importance of these new data is interpreted by docking studies using the X-ray structure of the GABA-B receptor...
April 7, 2018: Bioorganic & Medicinal Chemistry Letters
Valentina Vengeliene, Tatiane T Takahashi, Olga A Dravolina, Irina Belozertseva, Edwin Zvartau, Anton Y Bespalov, Rainer Spanagel
RATIONALE: Preclinical studies suggest that the GABAB receptor is a potential target for treatment of substance use disorders. However, recent clinical trials report adverse effects in patients treated with the GABAB receptor agonist baclofen and even question efficacy. How can the discrepancy between preclinical and clinical findings be explained? OBJECTIVE: To test efficacy and adverse effects of baclofen and the novel GABAB positive allosteric modulator (PAM) CMPPE in rat addiction models, which were developed in accordance with DSM...
April 12, 2018: Psychopharmacology
Gabriella Guerrini, Giovanna Ciciani, Simona Daniele, Claudia Martini, Camilla Costagli, Chiara Guarino, Silvia Selleri
A comparison between compounds with pyrazolo[1,5-a]pyrimidine structure (series 4-6) and pyrazolo[5,1-c][1,2,4]triazine core (series 9) as ligands at GABAA -receptor subtype, was evaluated. Moreover, for pyrazolotriazine derivatives having binding recognition, the interaction on recombinant rat α(1-3,5) GABAA receptor subtypes, was performed. Among these latter, emerge compounds 9c, 9k, 9l, 9m and 9n as α1-selective and 9h as α2-selective ligands.
April 4, 2018: Bioorganic & Medicinal Chemistry
Yoshimasa Kawarai, Hirokazu Tanaka, Tatsuya Kobayashi, Makio Shozu
Brain damage caused by hypoxic ischemic insult during the perinatal period causes hypoxic ischemic encephalopathies (HIEs). Therapeutic hypothermia is indicated for HIE, but since the therapeutic burden is large for its limited therapeutic effectiveness, another strategy is needed. Progesterone (P4) plays a neuroprotective role through the actions of its metabolite, allopregnanolone (Allo), on P4 receptor, GABA (γ-aminobutyric acid)A receptors or both. We examined the therapeutic potential of P4 using a newborn rat model of HIE...
April 10, 2018: Endocrinology
Nirja Chaudhari, Mitali Dawalbhakta, Laxmipriya Nampoothiri
BACKGROUND: GnRH is the master molecule of reproduction that is influenced by several intrinsic and extrinsic factors such as neurotransmitters and neuropeptides. Any alteration in these regulatory loops may result in reproductive-endocrine dysfunction such as the polycystic ovarian syndrome (PCOS). Although low dopaminergic tone has been associated with PCOS, the role of neurotransmitters in PCOS remains unknown. The present study was therefore aimed at understanding the status of GnRH regulatory neurotransmitters to decipher the neuroendocrine pathology in PCOS...
April 11, 2018: Reproductive Biology and Endocrinology: RB&E
Nela Durisic, Angelo Keramidas, Christine L Dixon, Joseph W Lynch
The GABAA receptor (GABAA R) α1 subunit A295D epilepsy mutation reduces the surface expression of α1A295D β2γ2 GABAA Rs via ER-associated protein degradation. Suberanilohydroxamic acid (SAHA, also known as Vorinostat) was recently shown to correct the misfolding of α1A295D subunits and thereby enhance the functional surface expression of α1A295D β2γ2 GABAA Rs. Here we investigated whether SAHA can also restore the surface expression of γ2 GABAA R subunits that incorporate epilepsy mutations (N40S, R43Q, P44S, R138G) known to reduce surface expression via ER-associated protein degradation...
2018: Frontiers in Molecular Neuroscience
Olga Babaev, Carolina Piletti Chatain, Dilja Krueger-Burg
Inhibitory neurotransmission plays a key role in anxiety disorders, as evidenced by the anxiolytic effect of the benzodiazepine class of γ-aminobutyric acid (GABA) receptor agonists and the recent discovery of anxiety-associated variants in the molecular components of inhibitory synapses. Accordingly, substantial interest has focused on understanding how inhibitory neurons and synapses contribute to the circuitry underlying adaptive and pathological anxiety behaviors. A key element of the anxiety circuitry is the amygdala, which integrates information from cortical and thalamic sensory inputs to generate fear and anxiety-related behavioral outputs...
April 9, 2018: Experimental & Molecular Medicine
Zhibing Tan, Heath L Robinson, Dong-Min Yin, Yu Liu, Fang Liu, Hongsheng Wang, Thiri W Lin, Guanglin Xing, Lin Gan, Wen-Cheng Xiong, Lin Mei
Top-down attention is crucial for meaningful behaviors and impaired in various mental disorders. However, its underpinning regulatory mechanisms are poorly understood. We demonstrate that the hippocampal-prefrontal synchrony associates with levels of top-down attention. Both attention and synchrony are reduced in mutant mice of ErbB4, a receptor of neuregulin-1. We used chemical genetic and optogenetic approaches to inactivate ErbB4 kinase and ErbB4+ interneurons, respectively, both of which reduce gamma-aminobutyric acid (GABA) activity...
April 3, 2018: Neuron
Bo Zhang, Lei Zhang, Lujue He, Xiaodong Yang, Yali Shi, Shaowei Liao, Shan Yang, Jiagao Cheng, Tianrui Ren
Fipronil is an efficient phenylpyrazole insecticide that acts on insect gamma-aminobutyric acid (GABA) receptors (GABARs) and has low toxicity to mammals but high toxicity to non-target organisms such as fish. To develop novel efficient low-toxicity insecticides, it is necessary to determine the detailed toxic mechanism at the molecular target level. In this work, methods including affinity chromatography, fluorescent-labeled binding assays and molecular modeling were integrated to explore the binding of fipronil to GABARs in fish (A...
April 7, 2018: Journal of Agricultural and Food Chemistry
Ken-Ichiro Hayashida, Masafumi Kimuram, James C Eisenach
Locus coeruleus (LC)-spinal noradrenergic projections are important to endogenous analgesic mechanisms and can be activated by local glutamate signaling in the LC. The current study examined the local glutamatergic, GABAergic, and noradrenergic influences on glutamate release in the LC and noradrenergic descending inhibition in rats 6 weeks after spinal nerve ligation (SNL). Intra-LC injection of the α2 adrenoceptor antagonist idazoxan or the group 2 metabotropic glutamate receptor (mGluR) antagonist (RS)-α-Methyl-4-tetrazolylphenylglycine (MTPG) increased withdrawal thresholds in SNL animals and this was reversed by the blockade of α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid (AMPA) receptors in the LC or α2-adrenoceptors in the spinal cord, but not in normal animals...
April 5, 2018: Neuroscience Letters
Nethrajeith Srinivasalu, Sally A McFadden, Callan Medcalf, Lena Fuchs, Jessica Chung, Gayle Philip, Andrea Richardson, Moeen Riaz, Paul N Baird
Purpose: Posterior scleral remodeling accompanies myopia. In guinea pigs developing myopia, the region around the optic nerve (peripapillary zone, PPZ) rapidly expands followed by inhibition in eye size in the periphery. We studied the differential gene expression in the sclera that accompanies these changes. Methods: Guinea pigs were form-deprived (FD) for 2 weeks to induce myopia, while the fellow eye served as a control. After 2 weeks, the PPZ and the peripheral temporal sclera were isolated in representative animals to extract the RNA...
March 1, 2018: Investigative Ophthalmology & Visual Science
Dmitry V Amakhin, Elena B Soboleva, Aleksey V Zaitsev
Cephalosporins are beta-lactam antibiotics that are extensively used in medical practice and are reported to cause epileptic seizures in some patients. The primary cause of cephalosporin-induced convulsions is believed to be their ability to block GABAa receptors. However, direct evidence for the involvement of this mechanism has not yet been provided. The present study aims to investigate the ability of two cephalosporins - cefepime and ceftriaxone - to block inhibitory synaptic transmission in entorhinal cortex slices of rats...
April 3, 2018: Biochemical and Biophysical Research Communications
Natasha C Pflanz, Anna W Daszkowski, Garrett L Cornelison, James R Trudell, S John Mihic
Benzodiazepines are positive allosteric modulators of the GABAA receptor (GABAA R), acting at the α-γ subunit interface to enhance GABAA R function. GABA or benzodiazepine binding induces distinct conformational changes in the GABAA R. The molecular rearrangements in the GABAA R following benzodiazepine binding remain to be fully elucidated. Using two molecular models of the GABAA R, we identified electrostatic interactions between specific amino acids at the α-γ subunit interface which were broken by, or formed after, benzodiazepine binding...
April 5, 2018: Journal of Biological Chemistry
Gabriele Ruffolo, Carlo Di Bonaventura, Pierangelo Cifelli, Cristina Roseti, Jinane Fattouch, Alessandra Morano, Cristina Limatola, Eleonora Aronica, Eleonora Palma, Anna Teresa Giallonardo
Epilepsy is one of the most common chronic neurological diseases, and its pharmacological treatment holds great importance for both physicians and national authorities, especially considering the high proportion of drug-resistant patients (about 30%). Lacosamide (LCM) is an effective and well-tolerated new-generation antiepileptic drug (AED), currently licensed as add-on therapy for partial-onset seizures. However, LCM mechanism of action is still a matter of debate, although its effect on the voltage sensitive sodium channels is by far the most recognized...
April 2, 2018: Neurobiology of Disease
Sara Guzzetti, Luciano Calzari, Lucia Buccarello, Valentina Cesari, Ivan Toschi, Stefania Cattaldo, Alessandro Mauro, Francesca Pregnolato, Silvia Michela Mazzola, Silvia Russo
Angelman syndrome (AS, MIM 105830) is a rare neurodevelopmental disorder affecting 1:10-20,000 children. Patients show moderate to severe intellectual disability, ataxia and absence of speech. Studies on both post-mortem AS human brains and mouse models revealed dysfunctions in the extra synaptic gamma-aminobutyric acid (GABA) receptors implicated in the pathogenesis. Taurine is a free intracellular sulfur-containing amino acid, abundant in brain, considered an inhibiting neurotransmitter with neuroprotective properties...
April 5, 2018: International Journal of Molecular Sciences
Mauro Sb Silva, Melanie Prescott, Rebecca E Campbell
Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS...
April 5, 2018: JCI Insight
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