Pharmacological Properties of GABA<sub>A</sub>Receptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Sergeeva, Olga A.; Andreeva, N. G.; Garret, Maurice; Scherer, Annette; Haas, Helmut L.

doi:10.1523/jneurosci.3209-04.2005

Cited by 60 publications

(69 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GABA A -R activation directly inhibits histaminergic cell firing rate [120,121], whereas GABA A -R inhibition increases TMN histamine release significantly [122]. Depending on GABA A -R-subunit expressions, histaminergic neurons displayed different sensitivities to GABA [123,124]. This may account for the functional heterogeneity of GABAergic responses displayed by histaminergic neurons following stimulation of the diagonal band of Broca, the antero-lateral hypothalamus, or the lateral preoptic area [120].…”

Section: Heterogeneity Of Histaminergic Neuronsmentioning

confidence: 99%

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Blandina¹,

Munari

Giannoni

et al. 2010

Future Neurol.

View full text Add to dashboard Cite

Much has been learned over the past 20 years about the role of histamine as a neurotransmitter. This brief article attempts to evaluate the progress accomplished in this field, and discusses the therapeutic potential of the H3 receptor (H3R). All histaminergic neurons are localized in the tuberomammillary nucleus of the posterior hypothalamus and project to almost all regions of the CNS. Histamine exerts its effect via interaction with specific receptors (H1R, H2R, H3R and H4R). Antagonists of both H1R and H2R have been successful as blockbuster drugs for treating allergic conditions and gastric ulcers. H4R is still awaiting better functional characterization, but the H3R is an attractive target for potential therapies of CNS disorders. Indeed, considerable interest was raised by reports that pharmacological blockade of H3Rs exerted procognitive effects in a variety of animal tasks analyzing different types of memory. In addition, blockade of H3Rs increased wakefulness and reduced bodyweight in animal models. Such findings hint at the potential use of H3R antagonists/inverse agonists for the treatment of Alzheimer’s disease and other dementias, attention-deficit hyperactivity disorder, obesity and sleep disorders. As a result, an increasing number of H3R antagonists/inverse agonists progress through the clinic for the treatment of a variety of conditions, including attention-deficit hyperactivity disorder, cognitive disorders, narcolepsy and schizophrenia. Moreover, the use of H3R antagonists/inverse agonists that weaken traumatic memories may alleviate disorders such as post-traumatic stress syndrome, panic attacks, specific phobias and generalized anxiety. The use of H3R ligands for the treatment of neurodegenerative disorders is demonstrated in several studies, indicating a role of the histamine neurons and H3Rs in neuroprotection. Recently, direct evidence demonstrated that histaminergic neurons are organized into functionally distinct circuits, impinging on different brain regions, and displaying selective control mechanisms. This could imply independent functions of subsets of histaminergic neurons according to their respective origin and terminal projections. The possibility that H3Rs control only some of those functions implies that H3R-directed therapies may achieve selective effects, with minimal side effects, and this may increase the interest regarding this class of drugs.

show abstract

Section: Heterogeneity Of Histaminergic Neuronsmentioning

confidence: 99%

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Blandina¹,

Munari

Giannoni

et al. 2010

Future Neurol.

View full text Add to dashboard Cite

show abstract

“…Evidence for the participation of the ⑀ subunit in neuronal inhibition is not yet definitive, although experiments suggest that it is expressed at synapses in the hypothalamus and NTS (Kasparov et al, 2001;Sergeeva et al, 2005). Furthermore, the native subunit partners in ⑀ subunit-containing receptors remain unknown.…”

Section: Physiological Implicationsmentioning

confidence: 99%

“…First, slow deactivation predicts long-lasting IPSCs. Indeed, IPSCs in ⑀ subunit-containing hypothalamic neurons are significantly longer than those in neurons that lack the ⑀ subunit (Sergeeva et al, 2005). Second, slow recovery from desensitization predicts that IPSCs should run down during repetitive activation, imparting a strong frequency dependence to synaptic inhibition Westbrook, 1995, 1996;Bianchi et al, 2002).…”

Section: Physiological Implicationsmentioning

confidence: 99%

“…First, these subunits have somewhat complementary distributions. The ⑀ subunit is concentrated in the hypothalamus and brainstem regions, such as the locus ceruleus and nucleus tractus solitarii (NTS), which tend to lack the ␦ subunit (Sinkkonen et al, 2000;Sergeeva et al, 2005). Second, the ␦ subunit increases the efficacy of neurosteroid modulation, whereas the ⑀ subunit reduces neurosteroid and anesthetic modulation (Davies et al, 1997;Belelli et al, 2002;Thompson et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…It is not known whether the ⑀ subunit participates in synaptic or extrasynaptic signaling, although the insensitivity of IPSPs in NTS neurons to benzodiazepines and of IPSCs in hypothalamic neurons to propofol may be attributable to ⑀ subunitcontaining synaptic receptors (Kasparov et al, 2001;Sergeeva et al, 2005). Whether synaptic or extrasynaptic, the kinetic properties conferred by ⑀ will determine its functional role.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABA_AReceptor

Wagner¹,

Goldschen-Ohm²,

Hales³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

GABA A receptors mediate synaptic and extrasynaptic inhibition. Native receptors consist of ␣ and ␤ subunits, which are required for function, and another "modulatory" subunit, for example, ␥, ␦, or ⑀. Of these, the ⑀ subunit has the most restricted distribution, confers resistance to neurosteroid and anesthetic modulation, and causes spontaneous channel opening. Little is known, however, about how ⑀ affects receptor kinetics, which in turn shape responses to both ambient and synaptic GABA exposure. Here, we expressed human ␣2␤1, ␣2␤1␥2, or ␣2␤1⑀ subunit combinations in human embryonic kidney 293 cells and used rapid solution exchange to study receptor kinetics in outside-out patches. The ⑀ subunit greatly slowed deactivation and recovery after brief GABA pulses. During long, saturating GABA pulses, the rate of desensitization was slower for ␣2␤1⑀ and ␣2␤1␥2 than for ␣2␤1. However, in ␣2␤1⑀, the final extent of desensitization was large compared with that of ␣2␤1␥2. Responses in ␣2␤1⑀, but not the others, were often followed by an "overshoot" above the baseline, suggesting that a fraction of channels are spontaneously open and are transiently silenced by receptor activation and subsequent desensitization. The baseline current and associated noise were reduced by picrotoxin, revealing that ⑀-containing channels are open ϳ4% of the time in the absence of GABA. These results suggest that, if ⑀-containing receptors are expressed at synapses, the synaptic currents would be long-lasting but may rundown quickly under high-frequency activation. In addition, silencing of spontaneous openings by desensitization raises the possibility that tonic inhibition mediated by ⑀-containing receptors may be regulated by phasic inhibition.

show abstract

GABA Receptors and the Pharmacology of Sleep

Wisden

Franks

2017

Handbook of Experimental Pharmacology

View full text Add to dashboard Cite

Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABA receptors. Pharmacogenetic experiments are leading to an understanding of the circuit mechanisms in the hypothalamus by which zolpidem and similar compounds induce sleep at α2βγ2-type GABA receptors. Drugs acting at more selective receptor types, for example, at receptors containing the α2 and/or α3 subunits expressed in hypothalamic and brain stem areas, could in principle be useful as hypnotics/anxiolytics. A highly promising sleep-promoting drug, gaboxadol, which activates αβδ-type receptors failed in clinical trials. Thus, for the time being, drugs such as zolpidem, which work as positive allosteric modulators at GABA receptors, continue to be some of the most effective compounds to treat primary insomnia.

show abstract

Pharmacological Properties of GABA_AReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Cited by 60 publications

References 32 publications

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABA_AReceptor

GABA Receptors and the Pharmacology of Sleep

Contact Info

Product

Resources

About

Pharmacological Properties of GABAAReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Cited by 60 publications

References 32 publications

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABAAReceptor

GABA Receptors and the Pharmacology of Sleep

Contact Info

Product

Resources

About

Pharmacological Properties of GABA_AReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABA_AReceptor