GABAB Receptor Chemistry and Pharmacology: Agonists, Antagonists, and Allosteric Modulators

Nieto, Ainhoa; Bailey, T. Liz; Kaczanowska, Katarzyna; McDonald, Patricia

doi:10.1007/7854_2021_232

Cited by 23 publications

(17 citation statements)

References 210 publications

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“…The amplitude of the initial Ca 2+ peak progressively decreased with further increases in agonist concentration. This dose–response relationship is quite different from the sigmoidal curve that has been described for GABA-evoked intracellular Ca 2+ signals in neurons and astrocytes [ 70 ], in which the Ca 2+ response is exclusively mediated by the metabotropic GABA B receptors [ 9 , 10 , 11 , 12 , 13 , 70 ]. The evidence, which is further illustrated below, that the endothelial Ca 2+ response to GABA is triggered by both GABA A and GABA B receptors could explain the peculiar profile of the dose–response relationship obtained in hCMEC/D3 cells.…”

Section: Discussioncontrasting

confidence: 59%

“…The highest Ca 2+ response was elicited by 1 µM GABA, although a robust increase in [Ca 2+ ] i could also be observed at higher agonist concentrations, i.e., 10 and 100 µM ( Figure 2 A,B). Nevertheless, 100 µM is the concentration range that has been exploited by most of the studies investigating how GABA induced intracellular Ca 2+ signals in neurons and astrocytes [ 9 , 10 , 11 , 12 , 13 ]. Furthermore, GABA concentrations at the synaptic cleft can increase up to 80 µM during neuronal activity [ 47 ], although they can reach over-saturating levels (≈3 mM) in response to tetanic stimulation [ 48 ].…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies showed that, in neurons and astrocytes, the Ca 2+ response to GABA was initiated by GABA B receptors and comprised a rapid Ca 2+ transient that is shaped by ER Ca 2+ release through InsP 3 Rs followed by SOCE [ 9 , 10 , 11 , 12 , 13 ]. The PLCβ signaling pathway has been invoked also as molecular driver of GABA-induced intracellular Ca 2+ signals outside the NVU [ 24 , 64 , 71 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although the metabotropic GABA B receptors are known to induce intracellular Ca 2+ signals both within [ 9 , 10 , 11 ] and outside [ 24 , 64 , 71 , 72 ] the NVU, the increase in the [Ca 2+ ] i whereby GABA regulates multiple endothelium-dependent functions in brain microvessels is mediated by the ionotropic GABA A receptors [ 17 , 20 ]. GABA A receptor activation by the selective agonist muscimol elicits an inward Cl − current in mouse cerebrovascular endothelial cells, thereby elevating the [Ca 2+ ] i [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…InsP 3 , in turn, binds to InsP 3 receptors (InsP 3 Rs), which are located on the endoplasmic reticulum (ER), and promotes Ca 2+ release into the cytoplasm. The following reduction in ER Ca 2+ levels activates a Ca 2+ entry pathway that resides on the plasma membrane, known as store-operated Ca 2+ entry (SOCE), which prolongs over time the Ca 2+ response to GABA B receptor stimulation [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells

Negri

Scolari

Vismara

et al. 2022

Cells

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Numerous studies recently showed that the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), can stimulate cerebral angiogenesis and promote neurovascular coupling by activating the ionotropic GABAA receptors on cerebrovascular endothelial cells, whereas the endothelial role of the metabotropic GABAB receptors is still unknown. Preliminary evidence showed that GABAA receptor stimulation can induce an increase in endothelial Ca2+ levels, but the underlying signaling pathway remains to be fully unraveled. In the present investigation, we found that GABA evoked a biphasic elevation in [Ca2+]i that was initiated by inositol-1,4,5-trisphosphate- and nicotinic acid adenine dinucleotide phosphate-dependent Ca2+ release from neutral and acidic Ca2+ stores, respectively, and sustained by store-operated Ca2+ entry. GABAA and GABAB receptors were both required to trigger the endothelial Ca2+ response. Unexpectedly, we found that the GABAA receptors signal in a flux-independent manner via the metabotropic GABAB receptors. Likewise, the full Ca2+ response to GABAB receptors requires functional GABAA receptors. This study, therefore, sheds novel light on the molecular mechanisms by which GABA controls endothelial signaling at the neurovascular unit.

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Section: Discussioncontrasting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells

Negri

Scolari

Vismara

et al. 2022

Cells

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Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities

Ye,

Wang,

et al. 2024

Medicinal Research Reviews

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Since the first discovery of antipsychotics in the 1950s, targeting dopaminergic drugs has manifested to well manage the positive symptoms of schizophrenia with limited efficacy for the negative and cognitive symptoms. In past decades, extensive efforts have been undertaken towards the development of innovative agents that can effectively stabilize the dopamine and serotonin systems or target to nondopaminergic pathways, leading to various promising drug candidates entering into clinical trials. Notably, the sigma‐2, 5‐HT2A, and α1A receptor antagonist roluperidone, as well as a fixed‐dose combination of the M1/4 receptor agonist KarXT, have been submitted for NDA applications. The dual agonist ulotaront, which targets TAAR1 and 5‐HT1A receptors, and the GlyT1 inhibitor iclepertin have advanced into phase 3 clinical trials. Nevertheless, satisfactory therapeutic strategies for schizophrenia remain elusive. This review highlights current clinical endeavors in developing novel chemical small‐molecule entities and fixed‐dose combinations for the treatment of schizophrenia since 2017, thus facilitating the efficient development of the next generation of antipsychotics.

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Signal detection of adverse events associated with gabapentinoid use for chronic pain

Kuo,

Polychronopoulou,

Raji

2023

Pharmacoepidemiology and Drug

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IntroductionGabapentinoids (GABA) prescribing as a potential and conceivably safer substitute for opioids has substantially increased. Understanding all potential adverse drug events (ADEs) associated with GABA will guide clinical decision‐making for pain management.MethodsA 20% sample of Medicare enrollees with new chronic pain diagnoses in 2017–2018 was selected. GABA users were those with >=30 consecutive days prescription in a year without opioid prescription. Opioid users were similarly defined. The control group used neither of these drugs. Propensity score match across three groups based on demographics and comorbidity was performed. We used proportional reporting ratio (PRR), Gamma Poisson Shrinker, and tree‐based scan statistic (TBSS) to detect ADEs within 3, 6, and 12 months of follow‐up.ResultsImmunity disorder was detected within 3 months of follow‐up by PRR compared to opioid use (PRR:2.33), and by all three methods compared to controls. Complications of transplanted organs/tissues and schizophrenia spectrum/other psychotic disorders were consistently detected by PRR and TBSS within 3 months. Skin disorders were detected by TBSS; and stroke was detected by PRR within 3 months compared to opioid use (PRR:4.74). Some malignancies were detected by PRR within 12 months. Other signals detected in GABA users were neuropathy and nerve disorders.ConclusionsOur study identified expected and unexpected ADE signals in GABA users. Neurological signals likely related to indications for GABA use. Signals for immunity, mental/behavior, and skin disorders were found in the FDA adverse event reporting system database. Unexpected signals of stroke and cancer require further confirmatory analyses to verify.

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GABAB Receptor Chemistry and Pharmacology: Agonists, Antagonists, and Allosteric Modulators

Cited by 23 publications

References 210 publications

GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells

GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells

Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities

Signal detection of adverse events associated with gabapentinoid use for chronic pain

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