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A high-resolution in vivo atlas of the human brain's benzodiazepine binding site of GABA_A receptors.

ABSTRACT: Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain and plays a key role in several brain functions and neuropsychiatric disorders such as anxiety, epilepsy, and depression. For decades, several in vivo and ex vivo techniques have been used to highlight the mechanisms of the GABA system, however, no studies have currently combined the techniques to create a high-resolution multimodal view of the GABA system. Here, we present a quantitative high-resolution in vivo atlas of the human brain benzodiazepine receptor sites (BZR) located on postsynaptic ionotropic GABA_A receptors (GABA_ARs), generated on the basis of in vivo [¹¹C]flumazenil Positron Emission Tomography (PET) data. Next, based on ex vivo autoradiography data, we transform the PET-generated atlas from binding values into BZR protein density. Finally, we examine the brain regional association between BZR protein density and ex vivo mRNA expression for the 19 subunits in the GABA_AR, including an estimation of the minimally required expression of mRNA levels for each subunit to translate into BZR protein. This represents the first publicly available quantitative high-resolution in vivo atlas of the spatial distribution of BZR densities in the healthy human brain. The atlas provides a unique neuroscientific tool as well as novel insights into the association between mRNA expression for individual subunits in the GABA_AR and the BZR density at each location in the brain.

SUBMITTER: Norgaard M

PROVIDER: S-EPMC8256681 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pyrazoloquinolinones (PQs) are a versatile class of GABAA receptor ligands. It has been demonstrated that high functional selectivity for certain receptor subtypes can be obtained by specific substitution patterns, but so far, no clear SAR rules emerge from the studies. As is the case for many GABAA receptor targeting chemotypes, PQs can interact with distinct binding sites on a given receptor pentamer. In pentamers of αβγ composition, such as the most abundant α1β2γ2 subtype, many PQs are high affinity binders of the benzodiazepine binding site at the extracellular α+/γ2- interfaces. There they display a functionally near silent, flumazenil-like allosteric activity. More recently, interactions with extracellular α+/β- interfaces have been investigated, where strong positive modulation can be steered toward interesting subtype preferences. The most prominent examples are functionally α6-selective PQs. Similar to benzodiazepines, PQs also seem to interact with sites in the transmembrane domain, mainly the sites used by etomidate and barbiturates. This promiscuity leads to potential contributions from multiple sites to net modulation. Developing ligands that interact exclusively with the extracellular α+/β- interfaces would be desired. Correlating functional profiles with binding sites usage is hampered by scarce and heterogeneous experimental data, as shown in our meta-analysis of aggregated published data. In the absence of experimental structures, bound states can be predicted with pharmacophore matching methods and with computational docking. We thus performed pharmacophore matching studies for the unwanted sites, and computational docking for the extracellular α1,6+/β3- interfaces. The results suggest that PQs interact with their binding sites with diverse binding modes. As such, rational design of improved ligands needs to take a complex structure-activity landscape with branches between sub-series of derivatives into account. We present a workflow, which is suitable to identify and explore potential branching points on the structure-activity landscape of any small molecule chemotype.

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A high-resolution in vivo atlas of the human brain's benzodiazepine binding site of GABA_A receptors.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

A high-resolution in vivo atlas of the human brain's benzodiazepine binding site of GABAA receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

A high-resolution in vivo atlas of the human brain's benzodiazepine binding site of GABA_A receptors.