Neurosteroid modulation of GABAA receptor function by independent action at multiple specific binding sites

2021 ◽  
Vol 19 ◽  
Author(s):  
Lei Wang ◽  
Douglas F. Covey ◽  
Gustav Akk ◽  
Alex S. Evers
Keyword(s):  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Specific Binding ◽  
Mammalian Brain ◽  
Allosteric Modulators ◽  
Receptor Function ◽  
Functional Effect ◽  
Specific Binding Sites ◽  
Independent Effects ◽  
Endogenous Modulators

: Neurosteroids are endogenous modulators of GABAA receptors that mediate anxiety, pain, mood and arousal. The 3-hydroxyl epimers, allopregnanolone (3α-OH) and epi-allopregnanolone (3β-OH) are both prevalent in mammalian brain and produce opposite effects on GABAA receptor function, acting as positive and negative allosteric modulators respectively. This Perspective provides a model to explain the actions of 3α-OH and 3β-OH neurosteroids. The model is based on evidence that the neurosteroid epimers bind to an overlapping subset of specific sites on GABAA receptors, with their net functional effect on channel gating being the sum of their independent effects at each site.

The binding of [3H]mepyramine to histamine H1 receptors in monkey brain

1985 ◽  
Vol 63 (6) ◽  
pp. 756-759 ◽  
Author(s):  
B. Bielkiewicz ◽  
D. A. Cook
Keyword(s):  
Binding Sites ◽  
Specific Binding ◽  
Histamine Receptor ◽  
Detailed Examination ◽  
Mammalian Brain ◽  
Binding Studies ◽  
Peripheral Tissues ◽  
Monkey Brain ◽  
Specific Binding Sites ◽  
Histamine H1 Receptors

Several laboratories have reported ligand binding studies using radioactive histamine H1 antagonists to label the H1 receptors in mammalian brain. We have extended these studies to a detailed examination of the binding of [3H]mepyramine to monkey brain and have shown that the distribution is similar to that in man, with specific binding sites being concentrated in the frontal cortex with relatively low binding to the pons and basal ganglia. The binding shows a single saturable component with a KD of about 1 nM and a Hill plot slope close to unity. These observations are the same for all structures tested. Comparison with data from other laboratories suggests that in this species, the histamine receptor is the same as that in peripheral tissues. From Ki values for various ligands and comparison of KD estimates in other species, the receptor seems to be essentially identical to the H1 receptor in central and peripheral tissues of the guinea pig and also to that in human brain. The rat and possibly the dog have minor differences from the monkey in terms of KD values for [3H]mepyramine binding.

scholarly journals Plasticity of GABAA Receptors during Pregnancy and Postpartum Period: From Gene to Function

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Valentina Licheri ◽  
Giuseppe Talani ◽  
Ashish A. Gorule ◽  
Maria Cristina Mostallino ◽  
Giovanni Biggio ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Postpartum Period ◽  
Neuronal Excitability ◽  
Receptor Expression ◽  
Neuroactive Steroids ◽  
Receptor Function ◽  
Pregnancy And Postpartum ◽  
Sudden Decrease ◽  
New Treatments

Pregnancy needs complex pathways that together play a role in proper growth and protection of the fetus preventing its premature loss. Changes during pregnancy and postpartum period include the manifold machinery of neuroactive steroids that plays a crucial role in neuronal excitability by local modulation of specific inhibitory receptors: the GABAA receptors. Marked fluctuations in both blood and brain concentration of neuroactive steroids strongly contribute to GABAA receptor function and plasticity. In this review, we listed several interesting results regarding the regulation and plasticity of GABAA receptor function during pregnancy and postpartum period in rats. The increase in brain levels of neuroactive steroids during pregnancy and their sudden decrease immediately before delivery are causally related to changes in the expression/function of specific GABAA receptor subunits in the hippocampus. These data suggest that alterations in GABAA receptor expression and function may be related to neurological and psychiatric disorders associated with crucial periods in women. These findings could help to provide potential new treatments for these women’s disabling syndromes.

scholarly journals Cholinergic Modulation of Sevoflurane Potency in Cortical and Spinal Networks In Vitro 

2007 ◽  
Vol 106 (6) ◽  
pp. 1147-1155 ◽  
Author(s):  
Christian Grasshoff ◽  
Berthold Drexler ◽  
Harald Hentschke ◽  
Horst Thiermann ◽  
Bernd Antkowiak
Keyword(s):  
Action Potential ◽  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Receptor Function ◽  
Action Potential Firing ◽  
Newborn Mice ◽  
Organophosphate Intoxication ◽  
Spontaneous Action Potential ◽  
Potential Firing ◽  
Spontaneous Action

Background Victims of organophosphate intoxication with cholinergic crisis may have need for sedation and anesthesia, but little is known about how anesthetics work in these patients. Recent studies suggest that cholinergic stimulation impairs gamma-aminobutyric acid type A (GABAA) receptor function. Because GABAA receptors are major targets of general anesthetics, the authors investigated interactions between acetylcholine and sevoflurane in spinal and cortical networks. Methods Cultured spinal and cortical tissue slices were obtained from embryonic and newborn mice. Drug effects were assessed by extracellular voltage recordings of spontaneous action potential activity. Results Sevoflurane caused a concentration-dependent decrease in spontaneous action potential firing in spinal (EC50=0.17+/-0.02 mM) and cortical (EC50=0.29+/-0.01 mM) slices. Acetylcholine elevated neuronal excitation in both preparations and diminished the potency of sevoflurane in reducing action potential firing in cortical but not in spinal slices. This brain region-specific decrease in sevoflurane potency was mimicked by the specific GABAA receptor antagonist bicuculline, suggesting that (1) GABAA receptors are major molecular targets for sevoflurane in the cortex but not in the spinal cord and (2) acetylcholine impairs the efficacy of GABAA receptor-mediated inhibition. The latter hypothesis was supported by the finding that acetylcholine reduced the potency of etomidate in depressing cortical and spinal neurons. Conclusions The authors raise the question whether cholinergic overstimulation decreases the efficacy of GABAA receptor function in patients with organophosphate intoxication, thereby compromising anesthetic effects that are mediated predominantly via these receptors such as sedation and hypnosis.

scholarly journals Allosteric Modulation of Haemocyanin Oxygen-affinity by L-Lactate And Urate in the Lobster Homarus Vulgaris: II. Characterization of Specific Effector Binding Sites

1992 ◽  
Vol 168 (1) ◽  
pp. 111-124 ◽  
Author(s):  
A. NIES ◽  
B. ZEIS ◽  
C. R. BRIDGES ◽  
M. K. GRIESHABER
Keyword(s):  
Binding Sites ◽  
Dissociation Constants ◽  
Specific Binding ◽  
Oxygen Affinity ◽  
Allosteric Modulators ◽  
Specific Binding Sites ◽  
Ligand Binding Sites ◽  
Specific Effector ◽  
Purine Ring

The haemocyanin of Homarus vulgaris possesses specific binding sites for L-lactate and urate, two allosteric modulators of haemocyanin oxygen-affinity. The affinities for both ligands have been determined. The dissociation constants, KD, are 0.87±0.26mmoll−1 for L-lactate and 0.03±0.01mmoll−1 for urate at 15°C and pH 8.0. The affinity of the haemocyanin is about 40 times larger for urate than for L-lactate. The stoichiometry of the binding is two ligands per dodecamer in both cases. l-Lactate does not compete with urate for its binding site and vice versa, indicating that the ligand binding sites are independent of each other. The specificity of urate binding to haemocyanin was investigated in competition experiments with allantoin, caffeine and hypoxanthine. The purine derivatives caffeine and hypoxanthine reduce the binding of urate to haemocyanin, whereas allantoin has no effect. Thus, the purine ring system seems to be essential for the binding of urate to haemocyanin. Note: To whom reprint requests should be addressed.

scholarly journals Specific Binding of Rubidium in Chlorella

1962 ◽  
Vol 45 (5) ◽  
pp. 959-977 ◽  
Author(s):  
Dan Cohen
Keyword(s):  
Active Transport ◽  
Binding Sites ◽  
Specific Binding ◽  
High Concentration ◽  
External Concentration ◽  
Specific Binding Sites ◽  
Dense Suspension ◽  
Concentration Of Ions ◽  
The Individual ◽  
A Site

Specific binding sites for potassium, which may be components of the carriers for active transport for K in Chlorella, were characterized by their capacity to bind rubidium. A dense suspension was allowed to take up Rb86 from a low concentration of Rb86 and a high concentration of ions which saturate non-specific sites. The amount bound was derived from the increase in the external concentration of Rb86 following addition of excess potassium. The sites were heterogeneous. The average affinity of Rb and various other ions for the sites was determined by plotting the degree of displacement of Rb86 against log molar concentration of the individual ions. Interpolation gave the concentration for 50 per cent displacement of Rb, which is inversely related to affinity. The order of affinity was not changed when the cells were frozen, or boiled either in water or in 70 per cent ethanol. The affinity is maximal for ions with a crystalline radius of 1.3 to 1.5 A and a high polarizability, and is not related to the hydrated radius or valency. It is suggested that binding groups in a site are rigidly arranged, the irregular space between them being 2.6 to 3.0 A across, so that affinity is high for ions of this diameter and high polarizability.

Studies of the uptake of macromolecules by cells. I. Uptake of proteins by cells of the Ehrlich–Lettré ascites carcinoma

1968 ◽  
Vol 46 (12) ◽  
pp. 1443-1450 ◽  
Author(s):  
Y. C. Choi ◽  
E. R. M. Kay
Keyword(s):  
Nucleic Acid ◽  
Cell Membrane ◽  
Binding Sites ◽  
Specific Binding ◽  
Protein Uptake ◽  
Specific Binding Sites ◽  
Model Protein ◽  
Uptake Process ◽  
Kinetics Of ◽  
Protein Treatment

The uptake of protein by cells of the Ehrlich–Lettré ascites carcinoma was characterized kinetically by using hemoglobin as a model protein. An attempt was made to show that the process is not an artefact due to nonspecific adsorption of protein to the cell membrane. The kinetics of the uptake process suggested that an interaction exists between the exogenous protein and specific binding sites on the membrane. Acetylation of hemoglobin enhanced the rate of uptake of this protein. Treatment of cells with neuraminidase, phospholipase A, and Pronase resulted in an inhibition of protein uptake. The experimental evidence for the uptake of hemoglobin was supported by evidence that L-serine-U-14C-labelled hemoglobin is transported into the cytoplasm and utilized subsequently, resulting in labelling of the nucleic acid nucleotides.

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