Native glycine receptor subtypes and their physiological roles
ABSTRACT The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. They are also found presynaptically, where they modulate neurotransmitter release. Functional GlyRs are formed from a total of five subunits (alpha1-alpha4, beta). Although alpha subunits efficiently form homomeric GlyRs in recombinant expression systems, homomeric alpha1, alpha3 and alpha4 GlyRs are weakly expressed in adult neurons. In contrast, alpha2 homomeric GlyRs are abundantly expressed in embryonic neurons, although their numbers decline sharply by adulthood. Numerous lines of biochemical, biophysical, pharmacological and genetic evidence suggest the majority of glycinergic neurotransmission in adults is mediated by heteromeric alpha1beta GlyRs. Immunocytochemical co-localisation experiments suggest the presence of alpha2beta, alpha3beta and alpha4beta GlyRs at synapses in the adult mouse retina. Immunocytochemical and electrophysiological evidence also implicates alpha3beta GlyRs as important mediators of glycinergic inhibitory neurotransmission in nociceptive sensory neuronal circuits in peripheral laminae of the spinal cord dorsal horn. It is yet to be determined why multiple GlyR synaptic subtypes are differentially distributed in these and possibly other locations. The development of pharmacological agents that can discriminate strongly between different beta subunit-containing GlyR isoforms will help to address this issue, and thereby provide important insights into a variety of central nervous system functions including retinal signal processing and spinal pain mechanisms. Finally, agents that selectively potentiate different GlyR isoforms may be useful as therapeutic lead compounds for peripheral inflammatory pain and movement disorders such as spasticity.
SourceAvailable from: Yong X. Wang[Show abstract] [Hide abstract]
ABSTRACT: Gelsemium, a small genus of flowering plant from the family Loganiaceae, comprises five species including the popular Gelsemium sempervirens Ait. and Gelsemium elegans Benth., which are indigenous to North America and China/East Asia, respectively. Approximately 120 alkaloids have been isolated and identified from Gelsemium, with the predominant indole alkaloids including gelsemine, koumine, gelsemicine, gelsenicine, gelsedine, sempervirine, koumidine, koumicine and humantenine. Gelsemine is the principal active alkaloid in G. sempervirens Ait., and koumine and gelsemine are the most and second-most dominant alkaloids in G. elegans Benth. Gelsemium extract and its active alkaloids serve a variety of biological functions, including neurobiological, immunosuppressive and antitumor effects, and have traditionally been used to treat pain, neuralgia, anxiety, insomnia, asthma, respiratory ailments and cancers. This review focuses on animal-based studies of Gelsemium as a pain treatment and its mechanism of action. In contrast to morphine, when administered intrathecally and systemically, koumine, gelsemine and gelsenicine have marked antinociception in inflammatory, neuropathic and bone cancer pains without inducing antinociceptive tolerance. Gelsemium and its active alkaloids may produce antinociception by activating the spinal α3 glycine/allopregnanolone pathway. The results of this review support the clinical use of Gelsemium and suggest that its active alkaloids may be developed to treat intractable and other types of pain, preferably after chemical modification. However, Gelsemium is a known toxic plant, and its toxicity limits its appropriate dosage and clinical use. To avoid or decrease the side/toxic effects of Gelsemium, an individual monomer of highly potent alkaloids must be selected, or alkaloids that exhibit greater α3 glycine receptor selectivity may be discovered or modified. Copyright © 2014 Elsevier B.V. All rights reserved.Fitoterapia 11/2014; 100C:35-43. DOI:10.1016/j.fitote.2014.11.002 · 2.22 Impact Factor
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ABSTRACT: Vitamin B12 (cobalamin, Cbl) deficiency can cause metabolic, hematological, and neurological abnormalities. Adequate levels of succinyl-coenzyme A (CoA) cannot be synthesized from methylmalonyl-CoA because of the decreased activity of the methylmalonyl-CoA mutase enzyme that uses Cbl as the cofactor. Succinyl-CoA synthesis deficiency leads to decreased heme synthesis and gluconeogenesis. The reason of growth retardation can be gluconeogenesis deficiency together with heme synthesis deficiency whereas the reason of the neurological abnormalities can be glycine increase in the tissue due to decreased heme synthesis. We present 7 infants diagnosed with severe nutritional Cbl deficiency and discuss the role of succinyl-CoA and glycine in the possible pathogenesis in this article. Patients brought to our clinic with a complaint of growth retardation and diagnosed with nutritional Cbl deficiency were included in the study. There were 5 females and 2 males. The mean age was 11 ± 2.30 (range 6-13) months. All patients had general muscular hypotonia and 4 had growth retardation. Neuromotor growth retardation was found in 4 of the children who had previously shown normal neuromotor development for age. The mean Cbl level was 83.8 ± 27.6 (45.6-114) pg/mL. The mean Cbl level of the mothers was 155 ± 56.6 (88-258) pg/mL. Six of the patients had anemia and 1 had thrombocytopenia. Mean corpuscular volume value was 91.5 ± 12.2 fL. Following treatment, the muscle tonus of the patients improved, the anemia and growth retardation decreased, and the lost neuromotor abilities were recovered. Severe nutritional Cbl deficiency is an important nutritional disease where complications can be prevented with early treatment. When evaluating the pathogenesis, it should be noted that nutritional Cbl deficiency is a succinyl-CoA synthesis deficiency.
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ABSTRACT: Dopamine is a critical neuromodulator that activates GPCRs in mammals or ligand-gated ion channels in invertebrates. The present study demonstrates that dopamine (0.1-10 mm) exerts novel, opposing effects on different populations of mammalian (rat) GABAA receptors. Using whole-cell patch-clamp electrophysiology, we observed direct dopamine-mediated inhibition of tonic-level (1 μm) GABA-evoked currents in untransfected striatal neurons that could be recapitulated in HEK293 cells containing α1β3 or α1β2γ2 subunits. Surprisingly, direct activation by dopamine was seen in the absence of GABA with α1β2γ2, α5β3γ2, or α1β3γ2 transfections. This activity was also present in α1β3γ2 receptors containing a mutant β3 subunit (H267A [(Z)β3]) insensitive to trace levels of inhibitory Zn(2+). Dopamine activation required β and γ subunits but not α subunits ((Z)β3γ2 EC50 value, 660 μm). Dopamine activity was fully blocked by picrotoxin but not GABAA competitive antagonists, and was strongly correlated with spontaneous receptor activity. We also report opposing effects of bicuculline and gabazine, such that bicuculline surprisingly activated non-α-containing (β3γ2) GABAA receptors, whereas gabazine suppressed spontaneous activity in these receptors. Our results suggest that dopamine may directly inhibit GABAA receptors that are both immediately adjacent to dopamine release sites in the striatum and activated by tonic GABA. Furthermore, synaptic/phasic release of dopamine may directly enhance signaling at some spontaneously active noncanonical GABAA receptors that lack α subunits. Copyright © 2015 the authors 0270-6474/15/353525-12$15.00/0.