GABA Potency at GABAA Receptors Found in Synaptic and Extrasynaptic Zones

Mortensen, Martin; Patel, Bijal; Smart, Trevor G.

doi:10.3389/fncel.2012.00001

Cited by 136 publications

(187 citation statements)

References 71 publications

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“…In agreement with previous reports (Karim et al, 2012;Jensen et al, 2013;Hoestgaard-Jensen et al, 2014), the receptors formed in a 4 b 1 d-and a 4 b 3 d-expressing oocytes also exhibited pronounced levels of constitutive activity (assessed by application of 10 mM picrotoxin; unpublished data). All in all, these basic functional properties of the receptors were in good agreement with those obtained in previous studies (Mortensen et al, 2011;Karim et al, 2012Karim et al, , 2013Hoestgaard-Jensen et al, 2013.…”

Section: Functional Characterization Of Methaqualone At Human Gaba a supporting

confidence: 80%

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

Hammer¹,

Bader²,

Ehnert³

et al. 2015

Mol Pharmacol

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In the present study, we have elucidated the functional characteristics and mechanism of action of methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone, Quaalude), an infamous sedative-hypnotic and recreational drug from the 1960s-1970s. Methaqualone was demonstrated to be a positive allosteric modulator at human a 1,2,3,5 b 2,3 g 2S GABA A receptors (GABA A Rs) expressed in Xenopus oocytes, whereas it displayed highly diverse functionalities at the a 4,6 b 1,2,3 d GABA A R subtypes, ranging from inactivity (Methaqualone did not interact with the benzodiazepine, barbiturate, or neurosteroid binding sites in the GABA A R. Instead, the compound is proposed to act through the transmembrane b(1) /a (-) subunit interface of the receptor, possibly targeting a site overlapping with that of the general anesthetic etomidate. The negligible activities displayed by methaqualone at numerous neurotransmitter receptors and transporters in an elaborate screening for additional putative central nervous system (CNS) targets suggest that it is a selective GABA A R modulator. The mode of action of methaqualone was further investigated in multichannel recordings from primary frontal cortex networks, where the overall activity changes induced by the compound at 1-100 mM concentrations were quite similar to those mediated by other CNS depressants. Finally, the free methaqualone concentrations in the mouse brain arising from doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity correlated fairly well with its potencies as a modulator at the recombinant GABA A Rs. Hence, we propose that the multifaceted functional properties exhibited by methaqualone at GABA A Rs give rise to its effects as a therapeutic and recreational drug.

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Section: Functional Characterization Of Methaqualone At Human Gaba a supporting

confidence: 80%

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

Hammer¹,

Bader²,

Ehnert³

et al. 2015

Mol Pharmacol

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“…2011; Chamma et al . 2012). Whether GPCR‐mediated regulation of KCC2 also modulates the ability of this transporter to regulate neuronal cell volume and/or its role in dendritic spine formation is likely to be an emerging avenue of investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Several excellent reviews have been recently published that comprehensively examine cellular KCC2 regulation (Chamma et al . 2012; Kahle et al . 2013; Kaila et al .…”

Section: Introductionmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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KCC2 is the central regulator of neuronal Cl− homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity. It is becoming increasingly clear that diverse cellular signals regulate KCC2 surface expression and function including neurotransmitters and neuromodulators. In the present review we explore the existing evidence that G‐protein‐coupled receptor (GPCR) signalling can regulate KCC2 activity in numerous regions of the nervous system including the hypothalamus, hippocampus and spinal cord. We present key evidence from the literature suggesting that GPCR signalling is a conserved mechanism for regulating chloride homeostasis. This evidence includes: (1) the activation of group 1 metabotropic glutamate receptors and metabotropic Zn2+ receptors strengthens GABAergic inhibition in CA3 pyramidal neurons through a regulation of KCC2; (2) activation of the 5‐hydroxytryptamine type 2A serotonin receptors upregulates KCC2 cell surface expression and function, restores endogenous inhibition in motoneurons, and reduces spasticity in rats; and (3) activation of A3A‐type adenosine receptors rescues KCC2 dysfunction and reverses allodynia in a model of neuropathic pain. We propose that GPCR‐signals are novel endogenous Cl− extrusion enhancers that may regulate KCC2 function.

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“…GABA A Rs are pentamers made up of a combination of 19 possible subunits (a [1][2][3][4][5][6], b [1][2][3], g [1][2][3], d, e, u, p, and r [1][2][3]). Most commonly, these receptors contain two a subunits, two b subunits, and one "tertiary" subunit (g, d, e, u, or p), although other arrangements occur (9,10). Among the a subunits, human ASM cell GABA A Rs contain only a4 or a5 subunits (human ASM cells also express b3, g2, d, and u subunits, thus expressing the necessary complement of subunits to form functional channels) (11).…”

mentioning

confidence: 99%

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Yocum

Gallos

Zhang

et al. 2016

Am J Respir Cell Mol Biol

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We previously demonstrated that airway smooth muscle (ASM) cells express g-aminobutyric acid A receptors (GABA A Rs), and that GABA A R agonists acutely relax ASM. Among the GABA A R a subunits, human ASM cells express only a4 and a5, providing the opportunity for selective pharmacologic targeting. Novel GABA A R-positive allosteric modulators designed for enhanced a4/a6 subunit selectivity were synthesized using iterative computational analyses (CMD-45 and XHe-III-74). Studies using oocyte heterologous expression systems confirmed that CMD-45 and XHe-III-74 led to significantly greater augmentation of currents induced by a 3% maximal effective concentration (EC 3 ) of GABA [EC 3 ]-induced currents in oocytes expressing a4 or a6 subunits (along with b3 and g2) compared with other a subunits. CMD-45 and XHe-III-74 also led to greater ex vivo relaxation of contracted wild-type mouse tracheal rings compared with tracheal rings from GABA A R a4 subunit (Gabra4) knockout mice. Furthermore, CMD-45 and XHe-III-74 significantly relaxed precontracted human ASM ex vivo, and, at a low concentration, both ligands led to a significant leftward shift in albuterolmediated ASM relaxation. In vivo, inhaled XHe-III-74 reduced respiratory system resistance in an asthmatic mouse model. Pretreatment of human ASM cells with CMD-45 and XHe-III-74 inhibited histamine-induced increases in intracellular calcium concentrations in vitro, an effect that was lost when calcium was omitted from the extracellular buffer, suggesting that inhibition of calcium influx due to alterations in plasma membrane potential may play a role in the mechanism of ASM relaxation. Selective targeting of the GABA A R a4 subunit with inhaled ligands may be a novel therapeutic pathway to treat bronchoconstriction, while avoiding sedative central nervous system effects, which are largely mediated by a1-3 subunit-containing GABA A Rs in the brain.

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GABA Potency at GABAA Receptors Found in Synaptic and Extrasynaptic Zones

Cited by 136 publications

References 71 publications

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

Regulation of neuronal chloride homeostasis by neuromodulators

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

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GABA Potency at GABAA Receptors Found in Synaptic and Extrasynaptic Zones

Cited by 136 publications

References 71 publications

A Multifaceted GABAAReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

A Multifaceted GABAAReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

Regulation of neuronal chloride homeostasis by neuromodulators

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Contact Info

Product

Resources

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A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)