The Glycine Receptor | ScienceGate

Background: : One of the best known to date GPCR class A (Rhodopsin) includes more than 100 orphan receptors for which the endogenous ligand is not known or is unclear. One of them is N-arachidonyl glycine receptor, named GPR18, a receptor that has been reported to be activated by Δ9-THC, endogenous cannabinoid receptors agonist anandamide and other cannabinoid receptor ligands suggesting it could be considered as third cannabinoid receptor. GPR18 activity, as well as its distribution might suggest usage of GPR18 ligands in treatment of endometriosis, cancer, and neurodegenerative disorders. Yet, so far only few GPR18 antagonists have been described, thus only ligand-based design approaches appear to be most useful to identify new ligands for this orphan receptor. Methods: : Main goal of this study, GPR18 inactive form homology model was built on the basis of the evolutionary closest homologous template: Human P2Y1 Receptor crystal structure. Results: : Obtained model was further evaluated and showed active/nonactive ligands differentiating properties with acceptable confidence. Moreover, it allowed for preliminary assessment of proteinligand interactions for a set of previously described ligands. Conclusion:: Thus collected data might serve as a starting point for a discovery of novel, active GPR18 blocking ligands.

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Targeted State Dependent Crosslinking Mass Spectrometry (CXMS) of the Human Alpha 1 Glycine Receptor (GLyR)

Biophysical Journal ◽

10.1016/j.bpj.2018.11.2120 ◽

2019 ◽

Vol 116 (3) ◽

pp. 392a

Author(s):

Kayce A. Tomcho ◽

Hannah E. Gering ◽

Rathna J. Veeramachaneni ◽

David J. Lapinsky ◽

Michael Cascio

Keyword(s):

Mass Spectrometry ◽

Glycine Receptor ◽

State Dependent

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Startle disease mutations reduce the agonist sensitivity of the human inhibitory glycine receptor.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)32229-9 ◽

1994 ◽

Vol 269 (29) ◽

pp. 18739-18742

Author(s):

S. Rajendra ◽

J.W. Lynch ◽

K.D. Pierce ◽

C.R. French ◽

P.H. Barry ◽

...

Keyword(s):

Glycine Receptor ◽

Startle Disease ◽

Disease Mutations

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Developmental-Dependent Action of Microtubule Depolymerization on the Function and Structure of Synaptic Glycine Receptor Clusters in Spinal Neurons

Journal of Neurophysiology ◽

10.1152/jn.00364.2003 ◽

2004 ◽

Vol 91 (2) ◽

pp. 1036-1049 ◽

Cited By ~ 27

Author(s):

Brigitte van Zundert ◽

Francisco J. Alvarez ◽

Juan Carlos Tapia ◽

Hermes H. Yeh ◽

Emilio Diaz ◽

...

Keyword(s):

Average Length ◽

Glycine Receptor ◽

Colchicine Treatment ◽

Morphological Properties ◽

Microtubule Depolymerization ◽

Spinal Neurons ◽

Functional Changes ◽

Microtubule Disruption ◽

Immature Neurons ◽

Mature Neurons

Microtubules have been proposed to interact with gephyrin/glycine receptors (GlyRs) in synaptic aggregates. However, the consequence of microtubule disruption on the structure of postsynaptic GlyR/gephyrin clusters is controversial and possible alterations in function are largely unknown. In this study, we have examined the physiological and morphological properties of GlyR/gephyrin clusters after colchicine treatment in cultured spinal neurons during development. In immature neurons (5-7 DIV), disruption of microtubules resulted in a 33 ± 4% decrease in the peak amplitude and a 72 ± 15% reduction in the frequency of spontaneous glycinergic miniature postsynaptic currents (mIPSCs) recorded in whole cell mode. However, similar colchicine treatments resulted in smaller effects on 10-12 DIV neurons and no effect on mature neurons (15-17 DIV). The decrease in glycinergic mIPSC amplitude and frequency reflects postsynaptic actions of colchicine, since postsynaptic stabilization of microtubules with GTP prevented both actions and similar reductions in mIPSC frequency were obtained by modifying the Cl- driving force to obtain parallel reductions in mIPSC amplitude. Confocal microscopy revealed that colchicine reduced the average length and immunofluorescence intensity of synaptic gephyrin/GlyR clusters in immature (approximately 30%) and intermediate (approximately 15%) neurons, but not in mature clusters. Thus the structural and functional changes of postsynaptic gephyrin/GlyR clusters after colchicine treatment were tightly correlated. Finally, RT-PCR, kinetic analysis and picrotoxin blockade of glycinergic mIPSCs indicated a reorganization of the postsynaptic region from containing both α2β and α1β GlyRs in immature neurons to only α1β GlyRs in mature neurons. Microtubule disruption preferentially affected postsynaptic sites containing α2β-containing synaptic receptors.

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