The GABAB Receptor—Structure, Ligand Binding and Drug Development

Evenseth, Linn Samira Mari; Gabrielsen, Mari; Sylte, Ingebrigt

doi:10.3390/molecules25133093

Cited by 64 publications

(42 citation statements)

References 110 publications

(246 reference statements)

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“…GABA B receptors are expressed in excitatory and inhibitory neurons both at pre- and post-synaptic terminals. They are heterodimeric, and pharmacological and physiological studies in both human and animal samples testified the existence of two receptor subtypes, GABA B1 (with two isoforms GABA B1a and GABA B1b ) and GABA B2 [ 119 , 121 ]. Pre-synaptic receptor modulates evoked neurotransmitter release regulating Ca 2+ influx, whereas post-synaptically, it controls neuronal K + current mediating slow and prolonged inhibitory postsynaptic potentials via adenylate cyclase pathway [ 119 ].…”

Section: Chemical Synapses Features In Temporal Lobe Epilepsymentioning

confidence: 99%

Synaptic Reshaping and Neuronal Outcomes in the Temporal Lobe Epilepsy

Ren

Curia

2021

IJMS

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Temporal lobe epilepsy (TLE) is one of the most common types of focal epilepsy, characterized by recurrent spontaneous seizures originating in the temporal lobe(s), with mesial TLE (mTLE) as the worst form of TLE, often associated with hippocampal sclerosis. Abnormal epileptiform discharges are the result, among others, of altered cell-to-cell communication in both chemical and electrical transmissions. Current knowledge about the neurobiology of TLE in human patients emerges from pathological studies of biopsy specimens isolated from the epileptogenic zone or, in a few more recent investigations, from living subjects using positron emission tomography (PET). To overcome limitations related to the use of human tissue, animal models are of great help as they allow the selection of homogeneous samples still presenting a more various scenario of the epileptic syndrome, the presence of a comparable control group, and the availability of a greater amount of tissue for in vitro/ex vivo investigations. This review provides an overview of the structural and functional alterations of synaptic connections in the brain of TLE/mTLE patients and animal models.

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Section: Chemical Synapses Features In Temporal Lobe Epilepsymentioning

confidence: 99%

Synaptic Reshaping and Neuronal Outcomes in the Temporal Lobe Epilepsy

Ren

Curia

2021

IJMS

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“…GABAergic neurons are the main source of GABA; additionally, synthesis occurs in glial cells (Angulo et al, 2008;Héja et al, 2012). The subtypes of GABA B receptors, GABA B1a/b and GABA B2, were shown to be located both pre-and postsynaptically, indicating a more modulatory function in the developing brain (López-Bendito et al, 2004;Evenseth et al, 2020). Various experimental models suggest that GABA B receptor antagonists modulate hippocampal-linked learning, memory, and behavior (Cryan and Kaupmann, 2005;Heaney and Kinney, 2016).…”

Section: Discussionmentioning

confidence: 99%

GABAB Receptor-Mediated Impairment of Intermediate Progenitor Maturation During Postnatal Hippocampal Neurogenesis of Newborn Rats

Gustorff

Scheuer

Schmitz

et al. 2021

Front. Cell. Neurosci.

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The neurotransmitter GABA and its receptors assume essential functions during fetal and postnatal brain development. The last trimester of a human pregnancy and early postnatal life involves a vulnerable period of brain development. In the second half of gestation, there is a developmental shift from depolarizing to hyperpolarizing in the GABAergic system, which might be disturbed by preterm birth. Alterations of the postnatal GABA shift are associated with several neurodevelopmental disorders. In this in vivo study, we investigated neurogenesis in the dentate gyrus (DG) in response to daily administration of pharmacological GABAA (DMCM) and GABAB (CGP 35348) receptor inhibitors to newborn rats. Six-day-old Wistar rats (P6) were daily injected (i.p.) to postnatal day 11 (P11) with DMCM, CGP 35348, or vehicle to determine the effects of both antagonists on postnatal neurogenesis. Due to GABAB receptor blockade by CGP 35348, immunohistochemistry revealed a decrease in the number of NeuroD1 positive intermediate progenitor cells and a reduction of proliferative Nestin-positive neuronal stem cells at the DG. The impairment of hippocampal neurogenesis at this stage of differentiation is in line with a significantly decreased RNA expression of the transcription factors Pax6, Ascl1, and NeuroD1. Interestingly, the number of NeuN-positive postmitotic neurons was not affected by GABAB receptor blockade, although strictly associated transcription factors for postmitotic neurons, Tbr1, Prox1, and NeuroD2, displayed reduced expression levels, suggesting impairment by GABAB receptor antagonization at this stage of neurogenesis. Antagonization of GABAB receptors decreased the expression of neurotrophins (BDNF, NT-3, and NGF). In contrast to the GABAB receptor blockade, the GABAA receptor antagonization revealed no significant changes in cell counts, but an increased transcriptional expression of Tbr1 and Tbr2. We conclude that GABAergic signaling via the metabotropic GABAB receptor is crucial for hippocampal neurogenesis at the time of rapid brain growth and of the postnatal GABA shift. Differentiation and proliferation of intermediate progenitor cells are dependent on GABA. These insights become more pertinent in preterm infants whose developing brains are prematurely exposed to spostnatal stress and predisposed to poor neurodevelopmental disorders, possibly as sequelae of early disruption in GABAergic signaling.

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“…This will allow the studying of the binding sites of potential drugs for neurodegenerative disorders in detail. Thus, both the GABAAR [88][89][90][91]; reviewed in [92], and the GABABR [93][94][95][96], reviewed in [97], were recently described using cryo-EM in full length in different conformations. Of note, one isoform of the GABABR is found in axons as it contains an axon-sorting signal [98] that has recently been found to bind to secreted APP, reducing vesicle release when bound [99].…”

Section: Discovering Details Of Synapses With Electron Microscopymentioning

confidence: 99%

Digging Deeper: Advancements in Visualization of Inhibitory Synapses in Neurodegenerative Disorders

Radulović

Sunkara

Maurer

et al. 2021

IJMS

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Recent research has provided strong evidence that neurodegeneration may develop from an imbalance between synaptic structural components in the brain. Lately, inhibitory synapses communicating via the neurotransmitters GABA or glycine have come to the center of attention. Increasing evidence suggests that imbalance in the structural composition of inhibitory synapses affect deeply the ability of neurons to communicate effectively over synaptic connections. Progressive failure of synaptic plasticity and memory are thus hallmarks of neurodegenerative diseases. In order to prove that structural changes at synapses contribute to neurodegeneration, we need to visualize single-molecule interactions at synaptic sites in an exact spatial and time frame. This visualization has been restricted in terms of spatial and temporal resolution. New developments in electron microscopy and super-resolution microscopy have improved spatial and time resolution tremendously, opening up numerous possibilities. Here we critically review current and recently developed methods for high-resolution visualization of inhibitory synapses in the context of neurodegenerative diseases. We present advantages, strengths, weaknesses, and current limitations for selected methods in research, as well as present a future perspective. A range of new options has become available that will soon help understand the involvement of inhibitory synapses in neurodegenerative disorders.

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The GABAB Receptor—Structure, Ligand Binding and Drug Development

Cited by 64 publications

References 110 publications

Synaptic Reshaping and Neuronal Outcomes in the Temporal Lobe Epilepsy

Synaptic Reshaping and Neuronal Outcomes in the Temporal Lobe Epilepsy

GABAB Receptor-Mediated Impairment of Intermediate Progenitor Maturation During Postnatal Hippocampal Neurogenesis of Newborn Rats

Digging Deeper: Advancements in Visualization of Inhibitory Synapses in Neurodegenerative Disorders

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