Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Sheryl S. Smith in Neurosteroid Effects in the Central Nervous System, 2003
As outlined below, neuroactive steroids have been explored as neuro-palliatives in a variety of settings, including use as anesthetics, anticonvulsants, anxiolytics, anti-depressants, neuroprotectants, and promnestics. Actions at GABAA receptors have enjoyed a central role in hypotheses regarding the behavioral effects of neuroactive steroids. However, it is worth bearing in mind that a necessary and sufficient role for GABAA receptors in complex behavioral states such as anesthesia, although widely accepted, is far from proven. Thus, other molecular targets of neuroactive steroids are reviewed briefly here. We keep the emphasis on those steroids also active at GABAA receptors, highlighting effects of other neuroactive steroids only when they serve to elucidate a particular point. When relevant, we review the actions of both GABA-potentiating and GABA-inhibiting steroids at these alternate targets. Another extensive treatment of many of these issues has recently been given.14Glycine Receptors
ENTRIES A–Z
Philip Winn in Dictionary of Biological Psychology, 2003
One of the inhibitory AMINO ACIDS; glycine and GABA are described as the two major fast neurotransmitters (see FAST NEUROTRANSMISSION) in the CENTRAL NERVOUS SYSTEM. Glycine is synthesized from SERINE in a reaction catalysed by serine hydroxymethyl-transferase. It is stored and used in a manner similar to other AMINO ACID NEUROTRANSMITTERS. It is found principally in the SPINAL CORD and in several brain structures, including the SUBSTANTIA NIGRA (where concentration is high), STRIATUM, RAPHE NUCLEI and various BRAINSTEM structures. Glycine receptors operate in a manner similar to GABA receptors. The well- known poison STRYCHNINE acts at glycine receptors.
Excitatory Actions of GSH on Neocortex
Christopher A. Shaw in Glutathione in the Nervous System, 2018
Glutathione is a particularly intriguing molecule from the perspective of information transfer in the mammalian nervous system. All three of its constituent amino acids are neuroactive. l-Glutamate is thought to be the endogenous neurotransmitter that activates a family of receptors (collectively referred to as glutamate receptors). l-Glutamate activates at least three ligand-gated ion channels, which are named on the basis of their preferred agonist as follows: N-methyl-d-aspartate receptors (NMDA receptors), α-amino-3-hydroxy-5-methyl-l,4-isoxazole propionate receptors (AMPA receptors), and high-affinity kainate receptors (Monaghan, Bridges, and Cotman 1989). In addition, glutamate also activates multiple G-protein-coupled receptors known collectively as glutamate metabotropic receptors (Bockaert, Pin, and Fagni 1993; Prezeau et al. 1994). Ionotropic glutamate receptors (i.e., glutamate-gated ion channels) are ubiquitous mediators of rapid synaptic excitation in the mammalian nervous system. l-Cysteine is an agonist at NMDA receptors (Pace et al. 1992; Olney et al. 1990) and is known to have excitotoxic properties (Olney et al. 1990). In the brain, glycine is a coagonist at NMDA receptors; on its own it does not activate these receptors, but it must be present for l-glutamate to cause channel opening (Johnson and Ascher 1987). In the spinal cord, glycine binds to and activates its own receptors (glycine receptors), which mediate rapid synaptic inhibition by virtue of the Cl- currents they gate (Kuhse, Betz, and Kirsch 1995; Betz et al. 1994). Thus, glutathione’s components have the potential to activate a wide variety of synaptic receptors, each with unique distributions and biophysical properties within the mammalian CNS.
Novel Sunifiram-carbamate hybrids as potential dual acetylcholinesterase inhibitor and NMDAR co-agonist: simulation-guided analogue design and pharmacological screening
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Khalid A. Agha, Nader E. Abo-Dya, Abdul Rashid Issahaku, Clement Agoni, Mahmoud E. S. Soliman, Eatedal H. Abdel-Aal, Zakaria K. Abdel-Samii, Tarek S. Ibrahim
Full activation of NMDARs requires agonist binding at two glycine and two glutamates on the tetrameric complex. Several experimental studies showed that the glycine site was likely to be fully occupied in vivo either by glycine itself or by D-serine.16 On the other hand, it was found that at some locations in the central nervous system, the glycine site is not fully saturated by glycine due to the activity of high-affinity glycine transporters (GlyT-1).17 The requirement for occupation of the glycine site has been derived from a number of observations that blocking glycine site in NMDAR exacerbates psychotic symptoms in schizophrenic individuals and impairs cognitive performance in healthy individuals.18 As a result of this, glycine binding site has attracted attention of many scientists as a potential target for safely elevating the activity of NMDARs.19 A number of potential strategies for enhancing NMDAR function and hence improving cognition via the glycine site had developed like administration of glycine but this strategy is limited by the high activity of GlyT-1, so effort is moved to develop GlyT-1 inhibitors like Pfizer sarcosine analogue CP-802079 (Figure 2). Limitation of this approach is activation of inhibitory glycine receptors.17,20 Another promising approach involves exogenous administration of partial agonists like Sunifiram.21,22
Cell signal transduction: hormones, neurotransmitters and therapeutic drugs relate to purine nucleotide structure
Published in Journal of Receptors and Signal Transduction, 2018
In comparison to GABAA [20] and glycine [24], antagonists of GABA [21,22] and glycine [23,26] receptors occlude the nucleotide aminouracil ring. The fits of glycine structures [23–26] focus on the nucleotide carbonyl group. Steroid Ru5135 [23] shares common sites of action with bicuculline [22] and strychnine [26] at GABAA and glycine receptors [27]. Antagonism at 5-HT3 receptors reduces GABA mediated inhibition and enhances transmission at glutamate receptors [28]. The glycine receptor is a main cell membrane target for extracellular cGMP [12]. Low glycine levels activate the glycine receptor, reducing activity in the glutamate/NO/cGMP pathway, whereas high levels enhance NMDA receptor activation [23]. In regard to the similar fits of acetylcholine, NMDA and GABAA structures, desensitization of α7-nicotinic receptors in rat hippocampal neurons selectively depresses GABAA receptors thereby enhancing responses at the NMDA receptor [29]. NMDA regulates GABAA function, in rat hypothalamic neurosecretory neurons, through presynaptic and postsynaptic mechanisms that are respectively dependent and independent of NO [30].
Strychnine, old still actual poison: description of poisoning cases reported to French Poison Control Centers over the past thirteen years
Published in Toxin Reviews, 2022
Camille Paradis, Denis Dondia, Audrey Nardon, Ingrid Blanc-Brisset, Arnaud Courtois, Jules-Antoine Vaucel, Magali Labadie
In the gray matter of the spinal cord, Renshaw cells function as inhibitory interneurons associated with an alpha motor neuron. Renshaw cells receive excitatory collaterals from the alpha motor neurone and thus, upon excitation, could release glycine to the alpha motor neurone in order to exert an inhibitory feedback and prevent alpha motor neurone firing. Strychnine is a potent antagonist of glycine receptors thus acting as an inhibitor of an inhibitory signal. This results in a motor disturbance characterized by an increase in muscle tone, associated with muscular hyperactivity. Clinical symptoms of poisoning appear suddenly and rapidly after ingestion, and begin with painful muscle contractures spontaneous or triggered by even the slightest stimulus, trismus, an opisthotonus (a position which the whole body is arched backward in hyperextension) and generalized convulsions for the severe forms. Importantly, during the course of poisoning, consciousness is retained. The clinical picture is complicated by major acidosis and rhabdomyolysis. Death occurs due to the paralysis of respiratory muscles or a cardiac arrest (Baud and Garnier 2017).
Related Knowledge Centers
- Brainstem
- Central Nervous System
- Glycine
- Inhibitory Postsynaptic Potential
- Amino Acid
- Spinal Cord
- Neurotransmitter
- Receptor
- Ligand-Gated Ion Channel
- Β-Alanine