Length of the TM3-4 loop of the glycine receptor modulates receptor desensitization
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Neurotransmitters such as acetylcholine (ACh) and glycine mediate fast synaptic neurotransmission by activating pentameric ligand-gated ion channels (LGICs). These receptors are allosteric transmembrane proteins that rapidly convert chemical messages into electrical signals. Neurotransmitters activate LGICs by interacting with an extracellular agonist-binding domain (ECD), triggering a tertiary/quaternary conformational change in the protein that results in the fast opening of an ion pore domain (IPD). However, the molecular mechanism that determines the fast opening of LGICs remains elusive. Here, we show by combining whole-cell and single-channel recordings of recombinant chimeras between the ECD of α7 nicotinic receptor (nAChR) and the IPD of the glycine receptor (GlyR) that only two GlyR amino acid residues of loop 7 (Cys-loop) from the ECD and at most five α7 nAChR amino acid residues of the M2-M3 loop (2-3L) from the IPD control the fast activation rates of the α7/Gly chimera and WT GlyR. Mutual interactions of these residues at a critical pivot point between the agonist-binding site and the ion channel fine-tune the intrinsic opening and closing rates of the receptor through stabilization of the transition state of activation. These data provide a structural basis for the fast opening of pentameric LGICs.
Cys-loop receptors
Light-gated ion channel
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GABBR1
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Ionotropic glutamate receptor
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Chloride channel
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Glycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination and sensory perception. Synaptic GlyRs are a heteromeric assembly of α and β subunits. Here we present cryo-EM structures of full-length zebrafish α1βBGlyR in the presence of an antagonist (strychnine), agonist (glycine), or agonist with a positive allosteric modulator (glycine/ivermectin). Each structure shows a distinct pore conformation with varying degrees of asymmetry. Molecular dynamic simulations found the structures were in a closed (strychnine) and desensitized states (glycine and glycine/ivermectin). Ivermectin binds at all five interfaces, but in a distinct binding pose at the β-α interface. Subunit-specific features were sufficient to solve structures without a fiduciary marker and to confirm the 4α:1β stoichiometry recently observed. We also report features of the extracellular and intracellular domains. Together, our results show distinct compositional and conformational properties of α1βGlyR and provide a framework for further study of this physiologically important channel.
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The literature data on glycine metabolism in neural tissue, mitochondrial Gly-cleaving system, Gly-catching system in neural and glial cells are summarized. The peculiarities of localization and distribution of specific glycine receptors and binding-sites in nervous tissue of mammals are described. Four types of glycine-binding receptors are described: own specific glycine receptor (Gly-R), ionotropic receptor, which binds N-methyl-D-aspartate selectively (NMDA-R), and ionotropic receptors of g-aminobutyrate (GABA A -R, GABA С -R). The feutures of glycine effects in neuroglial cultures are discussed
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Gamma-Aminobutyric Acid
Cys-loop receptors
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A P2Y receptor with 65% identity to mammalian P2Y6receptors, termed the p2y3 receptor, was recently cloned from a chick brain cDNA library and was proposed to represent a novel P2Y receptor subtype [Mol Pharmacol50:258–265 (1996)]. We cloned the turkey homologue of the chick p2y3 receptor, which shares high sequence identity (97.6%) with the chick receptor, and we stably expressed this receptor and the rat P2Y6 receptor in 1321N1 human astrocytoma cells. The capacities of uridine and adenine nucleotides to promote inositol phosphate accumulation and intracellular Ca2+ mobilization were determined for both receptors. UDP and 5-bromo-UDP were the most potent agonists and UTP was a less potent full agonist at both receptors. In contrast, adenine nucleotides and nucleotide derivatives were relatively more potent at the turkey p2y3 receptor than at the rat P2Y6 receptor. To determine whether the avian p2y3 receptor defined a new subtype of mammalian P2Y receptor or was a species homologue of the mammalian P2Y6 receptor, we screened two different human genomic libraries and a Southern blot with a p2y3 receptor probe, under low-stringency conditions that allowed the clear identification of the human P2Y6 receptor gene. Our data indicated that the human genome does not contain a receptor that is more homologous to the avian p2y3 receptor than the P2Y6 receptor. Taken together, these data further define the pharmacological selectivities of these UDP-selective receptors and strongly suggest that the avian p2y3 receptor is a species homologue of the mammalian P2Y6receptor.
Estrogen-related receptor gamma
P2Y receptor
Estrogen-related receptor alpha
GABBR1
Liver receptor homolog-1
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Harty, T. Patrick and Paul B. Manis. Kinetic analysis of glycine receptor currents in ventral cochlear nucleus. J. Neurophysiol. 79: 1891–1901, 1998. Glycine plays an important role as an inhibitory neurotransmitter in the ventral cochlear nucleus. However, little is known about the kinetic behavior of glycine receptors. The present study examines the kinetics of the native inhibitory glycine receptors in neurons of the ventral cochlear nucleus, using outside-out patches from acutely dissociated cells and a fast flow system. Steps into 1 mM glycine revealed fast phases of desensitization with time constants of 13 and 129 ms, that together produced a 40% reduction in current from the peak response. Slower desensitization phases also were observed. After removal of glycine, currents deactivated with two time constants of 15 and 68 ms, and these rates were independent of the glycine concentration between 0.2 and 1 mM. Recovery from desensitization was slow relative to desensitization itself. These results demonstrate that glycine receptors can exhibit faster rates of desensitization and deactivation than previously reported.
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The time course of currents mediated by native and recombinant glycine receptors was examined with a combination of rapid agonist applications to outside-out patches and single-channel recording. The deactivation time constant of currents evoked by brief, saturating pulses of glycine is profoundly affected by the chloride concentration on the intracellular side of the cell membrane. Deactivation was threefold slower when intracellular chloride was increased from a low level (10 m m ), similar to that observed in living mature neurons, to 131 m m (“symmetrical” chloride, often used in pipette internal solutions). Single-channel analysis revealed that high chloride has its greatest effect on the channel closing rate, slowing it by a factor of 2 compared with the value we estimated in the cell-attached mode (in which the channels are at physiological intracellular chloride concentrations). The same effect of chloride was observed when glycinergic evoked synaptic currents were recorded from juvenile rat spinal motoneurons in vitro , because the decay time constant was reduced from ∼7 ms to ∼3 ms when cells were dialyzed with 10 m m chloride intracellular recording solution. Our results indicate that the time course of glycinergic synaptic inhibition in intact neurons is much faster than is estimated by measurements in symmetrical chloride and can be modulated by changes in intracellular chloride concentration in the range that can occur in physiological or pathological conditions.
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Reversal potential
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