scholarly journals Site-specific effects of neurosteroids on GABAA receptor activation and desensitization

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yusuke Sugasawa ◽  
Wayland WL Cheng ◽  
John R Bracamontes ◽  
Zi-Wei Chen ◽  
Lei Wang ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Binding Sites ◽  
Specific Binding ◽  
Receptor Activation ◽  
Allosteric Modulation ◽  
Receptor Desensitization ◽  
Antagonist Activity ◽  
Competitive Antagonist ◽  
Site Specific ◽  
Specific Effects

This study examines how site-specific binding to three identified neurosteroid-binding sites in the α1β3 GABAA receptor (GABAAR) contributes to neurosteroid allosteric modulation. We found that the potentiating neurosteroid, allopregnanolone, but not its inhibitory 3β-epimer epi-allopregnanolone, binds to the canonical β3(+)–α1(-) intersubunit site that mediates receptor activation by neurosteroids. In contrast, both allopregnanolone and epi-allopregnanolone bind to intrasubunit sites in the β3 subunit, promoting receptor desensitization and the α1 subunit promoting effects that vary between neurosteroids. Two neurosteroid analogues with diazirine moieties replacing the 3-hydroxyl (KK148 and KK150) bind to all three sites, but do not potentiate GABAAR currents. KK148 is a desensitizing agent, whereas KK150 is devoid of allosteric activity. These compounds provide potential chemical scaffolds for neurosteroid antagonists. Collectively, these data show that differential occupancy and efficacy at three discrete neurosteroid-binding sites determine whether a neurosteroid has potentiating, inhibitory, or competitive antagonist activity on GABAARs.

scholarly journals Site-specific effects of neurosteroids on GABAA receptor activation and desensitization

2020 ◽  
Author(s):  
Yusuke Sugasawa ◽  
Wayland W. L. Cheng ◽  
John R. Bracamontes ◽  
Zi-Wei Chen ◽  
Lei Wang ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Binding Sites ◽  
Specific Binding ◽  
Receptor Activation ◽  
Allosteric Modulation ◽  
Receptor Desensitization ◽  
Antagonist Activity ◽  
Competitive Antagonist ◽  
Site Specific ◽  
Specific Effects

ABSTRACTThis study examines how site-specific binding to the three identified neurosteroid binding sites in the α1β3 GABAA receptor (GABAAR) contributes to neurosteroid allosteric modulation. We found that the potentiating neurosteroid, allopregnanolone, but not its inhibitory 3β-epimer epi-allopregnanolone, binds to the canonical β3(+)–α1(-) intersubunit site that mediates receptor activation by neurosteroids. In contrast, both allopregnanolone and epi-allopregnanolone bind to intrasubunit sites in the β3 subunit, promoting receptor desensitization and the α1 subunit promoting ligand-specific effects. Two neurosteroid analogues with diazirine moieties replacing the 3-hydroxyl (KK148 and KK150) bind to all three sites, but do not potentiate GABAAR currents. KK148 is a desensitizing agent, whereas KK150 is devoid of allosteric activity. These compounds provide potential chemical scaffolds for site-specific and general neurosteroid antagonists. Collectively, these data show that differential occupancy and efficacy at three discrete neurosteroid binding sites determine whether a neurosteroid has potentiating, inhibitory, or competitive antagonist activity on GABAARs.

scholarly journals Author response: Site-specific effects of neurosteroids on GABAA receptor activation and desensitization

2020 ◽  
Author(s):  
Yusuke Sugasawa ◽  
Wayland WL Cheng ◽  
John R Bracamontes ◽  
Zi-Wei Chen ◽  
Lei Wang ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Receptor Activation ◽  
Author Response ◽  
Site Specific ◽  
Specific Effects ◽  
Response Site

scholarly journals Analysis of GABAA Receptor Activation by Combinations of Agonists Acting at the Same or Distinct Binding Sites

2018 ◽  
Vol 95 (1) ◽  
pp. 70-81 ◽  
Author(s):  
Daniel J. Shin ◽  
Allison L. Germann ◽  
Douglas F. Covey ◽  
Joe Henry Steinbach ◽  
Gustav Akk
Keyword(s):  
Gabaa Receptor ◽  
Binding Sites ◽  
Receptor Activation

scholarly journals Theory of site-specific DNA-protein interactions in the presence of nucleosome roadblocks

2017 ◽  
Author(s):  
R. Murugan
Keyword(s):  
Protein Interactions ◽  
Binding Sites ◽  
Specific Binding ◽  
First Passage Time ◽  
Free Energy Barrier ◽  
Site Specific ◽  
Specific Binding Sites ◽  
Genome Wide ◽  
Diffusion Dynamics

AbstractWe show that nucleosomes can efficiently control the relative search times spent by transcription factors (TFs) on one- (1D) and three-dimensional (3D) diffusion routes towards locating their cognate sites on DNA. Our theoretical results suggest that the roadblock effects of nucleosomes are dependent on the relative position on DNA with respect to TFs and their cognate sites. Especially, nucleosomes exert maximum amount of hindrance to the 1D diffusion dynamics of TFs when they are positioned in between TFs and their cognate sites. The effective 1D diffusion coefficient (χTF) associated with the dynamics of TFs in the presence of nucleosome decreases with the free energy barrier (µ) associated the sliding dynamics of nucleosomes as . Subsequently the mean first passage time (ηL) that is required by TFs to scan L number of binding sites on DNA via 1D diffusion increases with μ as . When TFs move close to nucleosomes then they exhibit a typical sub-diffusive dynamics. Nucleosomes can enhance the search dynamics of TFs when TFs present in between nucleosomes and transcription factor binding sites (TFBS). The level of enhancement effects of nucleosomes seems to be much lesser than the level of retardation effects when nucleosomes present in between TFs and their cognate sites. These results suggest that nucleosome depleted regions around the cognate sites of TFs is mandatory for an efficient site-specific interactions of TFs with DNA. Remarkably the genome wide positioning pattern of TFs shows maximum at their specific binding sites and the positioning pattern of nucleosome shows minimum at the specific binding sites of TFs under in vivo conditions. This seems to be a consequence of increasing level of breathing dynamics of nucleosome cores and decreasing levels of fluctuations in the DNA binding domains of TFs as they move across TFBS. Since the extent of breathing dynamics of nucleosomes and fluctuations in the DBDs of TFs are directly linked with their respective 1D diffusion coefficients, the dynamics of TFs becomes slow as they approach their cognate sites so that TFs form tight site-specific complex. Whereas the dynamics of nucleosomes becomes rapid so that they pass through the cognate sites of TFs. Several in vivo datasets on genome wide positioning pattern of nucleosomes as well as TFs seem to agree well with our arguments. We further show that the condensed conformational state of DNA can significantly decrease the retarding effects of nucleosome roadblocks. The retarding effects of nucleosomes on the 1D diffusion dynamics of TFs can be nullified when the degree of condensation of the genomic DNA is such that it can permit a jump size associated with the dynamics of TFs beyond k > 150 bps.

scholarly journals Allosteric Modulation of GPCRs of Class A by Cholesterol

2021 ◽  
Vol 22 (4) ◽  
pp. 1953
Author(s):  
Jan Jakubík ◽  
Esam E. El-Fakahany
Keyword(s):  
Binding Sites ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Membrane Cholesterol ◽  
Extracellular Signals ◽  
High Affinity ◽  
Class A ◽  
Specific Effects ◽  
Induced Changes ◽  
G Protein Coupled

G-protein coupled receptors (GPCRs) are membrane proteins that convey extracellular signals to the cellular milieu. They represent a target for more than 30% of currently marketed drugs. Here we review the effects of membrane cholesterol on the function of GPCRs of Class A. We review both the specific effects of cholesterol mediated via its direct high-affinity binding to the receptor and non-specific effects mediated by cholesterol-induced changes in the properties of the membrane. Cholesterol binds to many GPCRs at both canonical and non-canonical binding sites. It allosterically affects ligand binding to and activation of GPCRs. Additionally, it changes the oligomerization state of GPCRs. In this review, we consider a perspective of the potential for the development of new therapies that are targeted at manipulating the level of membrane cholesterol or modulating cholesterol binding sites on to GPCRs.

scholarly journals Allosteric Modulation of GPCRs of Class A by Cholesterol

2021 ◽  
Author(s):  
Jan Jakubík ◽  
Esam E. El-Fakahany
Keyword(s):  
Binding Sites ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Membrane Cholesterol ◽  
Extracellular Signals ◽  
High Affinity ◽  
Class A ◽  
Specific Effects ◽  
Induced Changes ◽  
G Protein Coupled

G-protein coupled receptors (GPCRs) are membrane proteins that convey extracellular signals to the cellular milieu. They represent a target for more than 30 % of currently marketed drugs. Here we review the effects of membrane cholesterol on the function of GPCRs of Class A. We review both the specific effects of cholesterol mediated via its direct high-affinity binding to the receptor and non-specific effects mediated by cholesterol-induced changes in the properties of the membrane. Cholesterol binds to many GPCRs at both canonical and non-canonical binding sites. It allosterically affects ligand binding to and activation of GPCRs. Also, it changes the oligomerization state of GPCRs. In this review, we consider a perspective of the potential for the development of new therapies that are targeted at manipulating the level of membrane cholesterol or modulating cholesterol binding sites on to GPCRs.

Specific binding of a phenyl-pyridazinium derivative endowed with GABAA receptor antagonist activity to rat brain

1986 ◽  
Vol 25 (11) ◽  
pp. 1279-1283 ◽  
Author(s):  
M. Heaulme ◽  
J.P. Chambon ◽  
R. Leyris ◽  
C.G. Wermuth ◽  
K. Biziere
Keyword(s):  
Receptor Antagonist ◽  
Rat Brain ◽  
Gabaa Receptor ◽  
Specific Binding ◽  
Antagonist Activity ◽  
Gabaa Receptor Antagonist
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