scholarly journals Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two  distinct mechanisms            

2022 ◽  
Author(s):  
Konstantina Bampali ◽  
Filip Koniuszewski ◽  
Luca Silva ◽  
Sabah Rehman ◽  
Florian Vogel ◽  
...  
Keyword(s):  
Binding Site ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtypes ◽  
Therapeutic Effects ◽  
Functional Studies ◽  
Tricyclic Compounds ◽  
Electrode Voltage ◽  
Functional Inhibition ◽  
Gaba Receptor Subunits

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal a5 subunit-containing GABA receptors. The purpose of this study is to investigate tricyclic compounds in a5 subunit-containing receptor subtypes. Experimental Approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the a5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine exert functional inhibition on multiple GABA receptor subtypes, including a5-containing ones. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in a5 GABA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The C C C C C C site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA receptor subtypes.

scholarly journals Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two  distinct mechanisms            

2022 ◽  
Author(s):  
Konstantina Bampali ◽  
Filip Koniuszewski ◽  
Luca Silva ◽  
Sabah Rehman ◽  
Florian Vogel ◽  
...  
Keyword(s):  
Binding Site ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtypes ◽  
Therapeutic Effects ◽  
Functional Studies ◽  
Tricyclic Compounds ◽  
Electrode Voltage ◽  
Functional Inhibition ◽  
Gaba Receptor Subunits

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal a5 subunit-containing GABA receptors. The purpose of this study is to investigate tricyclic compounds in a5 subunit-containing receptor subtypes. Experimental Approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the a5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine exert functional inhibition on multiple GABA receptor subtypes, including a5-containing ones. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in a5 GABA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The CPZ site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA receptor subtypes.

scholarly journals Interactions of tricyclic antipsychotic and antidepressant medications with a novel binding site in GABAA receptors

2021 ◽  
Author(s):  
Konstantina Bampali ◽  
Filip Koniuszewski ◽  
Luca Silva ◽  
Sabah Rehman ◽  
Florian Vogel ◽  
...  
Keyword(s):  
Binding Site ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Antidepressant Drugs ◽  
Receptor Subtypes ◽  
Specific Information ◽  
Therapeutic Effects ◽  
The Novel ◽  
Antidepressant Medications ◽  
Functional Studies

Background and Purpose: Many psychotherapeutic drugs including clozapine have a polypharmacological profile and act on GABA receptors, where subtype-specific information is often lacking. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit containing GABA receptors. Experimental Approach: Functional studies of GABA modulatory effects by antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Computational ligand analysis complemented the functional and mutational data. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine have negative modulatory effects on multiple GABA receptor subtypes, including α5-containing. On the latter we show negative modulatory effects for five additional antipsychotic and antidepressant drugs. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in α5 GABA receptor subunits. Conclusion and Implications: Our findings support previous studies suggesting a link between some of the therapeutic effects of clozapine and its negative modulatory action on certain GABA receptor subtypes. The novel site we describe in this study is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology.

Pathway-Specific Targeting of GABAA Receptor Subtypes to Somatic and Dendritic Synapses in the Central Amygdala

2001 ◽  
Vol 86 (2) ◽  
pp. 717-723 ◽  
Author(s):  
Andrew J. Delaney ◽  
Pankaj Sah
Keyword(s):  
Gaba Receptors ◽  
Large Amplitude ◽  
Gaba Receptor ◽  
Small Amplitude ◽  
Inhibitory Synapses ◽  
Receptor Subtypes ◽  
Central Amygdala ◽  
Low Concentrations ◽  
Gabaa Receptor Subtypes ◽  
Minimal Stimulation

Neurons in the central amygdala express two distinct types of ionotropic GABA receptor. One is the classical GABAA receptor that is blocked by low concentrations of bicuculline and positively modulated by benzodiazepines. The other is a novel type of ionotropic GABA receptor that is less sensitive to bicuculline but blocked by the GABAC receptor antagonist (1,2,5,6-tetrohydropyridine-4-yl) methylphosphinic acid (TPMPA) and by benzodiazepines. In this study, we examine the distribution of these two receptor types. Recordings of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) showed a wide variation in amplitude. Most events had amplitudes of <50 pA, but a small minority had amplitudes >100 pA. Large-amplitude events also had rise times faster than small-amplitude events. Large-amplitude events were fully blocked by 10 μM bicuculline but unaffected by TPMPA. Small amplitude events were partially blocked by both bicuculline and TPMPA. Focal application of hypertonic sucrose to the soma evoked large-amplitude mIPSCs, whereas focal dendritic application of sucrose evoked small-amplitude mIPSCs. Thus inhibitory synapses on the dendrites of neurons in the central amygdala express both types of GABA receptor, but somatic synapses expressed purely GABAA receptors. Minimal stimulation revealed that inhibitory inputs arising from the laterally located intercalated cells innervate dendritic synapses, whereas inhibitory inputs of medial origin innervated somatic inhibitory synapses. These results show that different types of ionotropic GABA receptors are targeted to spatially and functionally distinct synapses. Thus benzodiazepines will have different modulatory effects on different inhibitory pathways in the central amygdala.

scholarly journals Subunit compositions of GABAA receptors determining the diversity of physiological processes and neurotropic properties of medicines

2021 ◽  
Vol 25 (1) ◽  
pp. 13-23
Author(s):  
M.Ya. Golovenko
Keyword(s):  
Binding Site ◽  
Gaba Receptor ◽  
Synaptic Activity ◽  
Mammalian Brain ◽  
Receptor Subtypes ◽  
Gamma Aminobutyric Acid ◽  
Wide Range ◽  
Potential Applications ◽  
Α1 Receptors ◽  
Subtype Selective

Gamma-aminobutyric acid (GABA) became known as a potentially important chemical in the brain 50 years ago, but its significance as a neurotransmitter was fully found 16 years later. It is now known that at least 40 % of the inhibitory synaptic activity in the mammalian brain is accounted for by GABA.  Аim. To analyze achievements in the study of the physiological and pharmacological role of GABA receptor subtypes, their potential applications in drug development and updated information on the clinical development of subtype-selective GABA receptor compounds.  Results. The GABAA-receptor complex (GABA-RC) is ligand-gated ion channels with chloride conductance. These receptors contain α, β, and γ subunits, but δ, ε, θ, and ρ can be also present. The GABA binding site is located at the interface between α and β subunits where a number of important amino acids are also found. GABA-RC is sensitive to a wide range of drugs, e.g. benzodiazepines (BDZ), which are often used for their sedative/hypnotic and anxiolytic effects. Classical BDZ interact non-selectively with α1,3,5 βγ2 GABA-RС in the binding site located at the α+γ− interface.  Conclusions.  In addition to the potent and rapid pharmacotherapeutic action BDZ also possess some addictive potential (drug dependence), which appears after the interaction of molecules with α1-receptors. Using the selective targeting to separate subgroups not only the main effect of BDZ without side effects can be provided, but also one can use this approach in creating new analgesic medicines; we have demonstrated it on the example of propoxazepam (full agonist GABA-R).

Therapeutically leveraging GABAA receptors in cancer

2021 ◽  
Vol 246 (19) ◽  
pp. 2128-2135
Author(s):  
Debanjan Bhattacharya ◽  
Vaibhavkumar S Gawali ◽  
Laura Kallay ◽  
Donatien K Toukam ◽  
Abigail Koehler ◽  
...  
Keyword(s):  
Gaba Receptors ◽  
Brain Function ◽  
Gaba Receptor ◽  
Krebs Cycle ◽  
Type A ◽  
Therapeutic Benefit ◽  
Disease States ◽  
The Central Nervous System ◽  
Pathological Disease ◽  
Gaba Receptor Subunits

γ-aminobutyric acid or GABA is an amino acid that functionally acts as a neurotransmitter and is critical to neurotransmission. GABA is also a metabolite in the Krebs cycle. It is therefore unsurprising that GABA and its receptors are also present outside of the central nervous system, including in immune cells. This observation suggests that GABAergic signaling impacts events beyond brain function and possibly human health beyond neurological disorders. Indeed, GABA receptor subunits are expressed in pathological disease states, including in disparate cancers. The role that GABA and its receptors may play in cancer development and progression remains unclear. If, however, those cancers have functional GABA receptors that participate in GABAergic signaling, it raises an important question whether these signaling pathways might be targetable for therapeutic benefit. Herein we summarize the effects of modulating Type-A GABA receptor signaling in various cancers and highlight how Type-A GABA receptors could emerge as a novel therapeutic target in cancer.

scholarly journals Heterogeneous expression of GABA receptor‐like subunits LCCH3 and GRD reveals functional diversity of GABA receptors in the honeybee Apis mellifera

2020 ◽  
Vol 177 (17) ◽  
pp. 3924-3940
Author(s):  
Christopher Henry ◽  
Thierry Cens ◽  
Pierre Charnet ◽  
Catherine Cohen‐Solal ◽  
Claude Collet ◽  
...  
Keyword(s):  
Apis Mellifera ◽  
Functional Diversity ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Heterogeneous Expression

Subcellular Localization and Complements of GABAA and GABAC Receptors on Bullfrog Retinal Bipolar Cells

2000 ◽  
Vol 84 (2) ◽  
pp. 666-676 ◽  
Author(s):  
Jiu-Lin Du ◽  
Xiong-Li Yang
Keyword(s):  
Subcellular Localization ◽  
Receptor Antagonist ◽  
Gaba Receptor ◽  
Drug Application ◽  
Bipolar Cells ◽  
Visual Signals ◽  
Receptor Subtypes ◽  
Inner Retina ◽  
Axon Terminals ◽  
Retinal Bipolar Cells

γ-Aminobutyric acid (GABA) receptors on retinal bipolar cells (BCs) are highly relevant to spatial and temporal integration of visual signals in the outer and inner retina. In the present work, subcellular localization and complements of GABAA and GABACreceptors on BCs were investigated by whole cell recordings and local drug application via multi-barreled puff pipettes in the bullfrog retinal slice preparation. Four types of the BCs (types 1–4) were identified morphologically by injection of Lucifer yellow. According to the ramification levels of the axon terminals and the responses of these cells to glutamate (or kainate) applied at their dendrites, types 1 and 2 of BCs were supposed to be off type, whereas types 3 and 4 of BCs might be on type. Bicuculline (BIC), a GABAA receptor antagonist, and imidazole-4-acetic acid (I4AA), a GABAC receptor antagonist, were used to distinguish GABA receptor-mediated responses. In all BCs tested, not only the axon terminals but also the dendrites showed high GABA sensitivity mediated by both GABAA and GABACreceptors. Subcellular localization and complements of GABAA and GABAC receptors at the dendrites and axon terminals were highly related to the dichotomy of offand on BCs. In the case of off BCs, GABAA receptors were rather evenly distributed at the dendrites and axon terminals, but GABAC receptors were predominantly expressed at the axon terminals. Moreover, the relative contribution of GABAC receptors to the axon terminals was prevalent over that of GABAA receptors, while the situation was reversed at the dendrites. In the case of on BCs, GABAA and GABAC receptors both preferred to be expressed at the axon terminals; relative contributions of these two GABA receptor subtypes to both the sites were comparable, while GABAC receptors were much less expressed than GABAA receptors. GABAA, but not GABAC receptors, were expressed clusteringly at axons of a population of BCs. In a minority of BCs, I4AA suppressed the GABAC responses at the dendrites, but not at the axon terminal, implying that the GABAC receptors at these two sites may be heterogeneous. Taken together, these results suggest that GABAA and GABAC receptors may play different roles in the outer and inner retina and the differential complements of the two receptors on off and on BCs may be closely related to physiological functions of these cells.

scholarly journals Striatal Neurodegeneration that Mimics Huntington’s Disease Modifies GABA-induced Currents

2018 ◽  
Vol 8 (12) ◽  
pp. 217
Author(s):  
Jorge Flores-Hernández ◽  
Jeanette Garzón-Vázquez ◽  
Gustavo Hernández-Carballo ◽  
Elizabeth Nieto-Mendoza ◽  
Evelyn Ruíz-Luna ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtype ◽  
Medium Spiny Neurons ◽  
Nitropropionic Acid ◽  
Spiny Neurons ◽  
Excitotoxic Damage ◽  
Induced Currents

Huntington’s Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium spiny neurons (MSNs) from excitotoxic damage. This study evaluates whether mitochondrial inhibition with 3-NP that mimics the early stages of HD, modifies the kinetics and pharmacology of GABA receptors in patch clamp recorded dissociated MSNs cells. The results show that MSNs from mice treated with 3-NP exhibited differences in GABA-induced dose-response currents and pharmacological responses that suggests the presence of GABAC receptors in MSNs. Furthermore, there was a reduction in the effect of the GABAC antagonist that demonstrates a lessening of this GABA receptor subtype activity as a result of mitochondria inhibition.

Effect of SR-49059, a vasopressin V1a antagonist, on human vascular smooth muscle cells

1995 ◽  
Vol 268 (1) ◽  
pp. H404-H410 ◽  
Author(s):  
C. Serradeil-Le Gal ◽  
J. M. Herbert ◽  
C. Delisee ◽  
P. Schaeffer ◽  
D. Raufaste ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Specific Binding ◽  
Muscle Cells ◽  
Maximal Response ◽  
Receptor Subtypes ◽  
Functional Studies ◽  
Antagonist Binding

The effects of SR-49059, a new nonpeptide and selective arginine vasopressin (AVP) V1a antagonist, were investigated in binding and functional studies on cultured human aortic vascular smooth muscle cells (VSMC). Characterization of human vascular V1a receptors, using a specific V1a radioiodinated ligand, showed that [125I]-linear AVP antagonist binding to human VSMC membranes was time dependent, reversible, and saturable. A single population of high-affinity binding sites (apparent equilibrium dissociation constant = 15 +/- 6 pM; maximum binding density = 36 +/- 5 fmol/mg protein, i.e., approximately 3,000 sites/cell) with the expected V1a profile was identified. Exposure of these cells to AVP dose-dependently produced cytosolic free [Ca2+] increase [AVP concentration required to obtain a half-maximal response (EC50) = 23 +/- 9 nM] and proliferation (EC50 = 3.2 +/- 0.5 nM). SR-49059 strongly and stereospecifically inhibited [125I]-linear AVP antagonist binding to VSMC V1a receptors [inhibition constant (Ki) = 1.4 +/- 0.3 nM], AVP-evoked Ca2+ increase [concentration of inhibitor required to obtain 50% inhibition of specific binding (IC50) = 0.41 +/- 0.06 nM], and the mitogenic effects induced by 100 nM AVP (IC50 = 0.83 +/- 0.04 nM). OPC-21268, another nonpeptide V1a antagonist, was more than two orders of magnitude less potent than SR-49059 in these models. However, the consistent affinity (Ki = 138 +/- 21 nM) and activity found with OPC-21268 on human VSMC in comparison with the inactivity already observed for other human V1a receptors (liver, platelets, adrenals, and uterus) strongly suggested the existence of human AVP V1a-receptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

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