Regulation of GABA<sub>A</sub>Receptor Subunit Expression by Pharmacological Agents

Uusi‐Oukari, Mikko; Korpi, Esa R.

doi:10.1124/pr.109.002063

Cited by 188 publications

(179 citation statements)

References 281 publications

(506 reference statements)

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“…In some cells expression of more than eight different isoforms has been demonstrated [5]. Throughout the CNS some subunits are broadly expressed, while others exhibit more restricted expression profile [17,18]. For example, the most abundant α1 subunit is expressed almost ubiquitously in the brain, α5 is highly expressed in the hippocampus, α6 subunit is expressed only in granule cells of the cerebellum, while ρ-subunits, the major molecular components of the formerly called GABAC receptors, are expressed mainly in the retina [19][20][21][22].…”

Section: Gabaa Receptors and Their Subunitsmentioning

confidence: 99%

“…GABAA receptors are therefore widely used in the treatment of anxiety disorders, insomnia, epilepsy, restlessness, and aggressive behaviours [17,68] GABAergic inhibition contributes to the pathophysiology of autism spectrum disorders.…”

Section: Modulation Of Gabaa Receptors By Pharmacological Agentsmentioning

confidence: 99%

“…Namely, besides binding site(s) for GABA, GABAA receptors possess binding sites for a variety of clinically important substances, such as benzodiazepines and benzodiazepine-site ligands, barbiturates, intravenous and volatile anesthetics, ethanol and neuroactive steroids, all of which achieve at least some of their pharmacological effects after binding to GABAA receptor complex [6,17,57]. These drugs modulate effects of GABA and affect GABAergic transmission, exerting a wide spectrum of pharmacological effects and inducing numerous conformational states of GABAA receptors.…”

Section: Modulation Of Gabaa Receptors By Pharmacological Agentsmentioning

confidence: 99%

“…Expression of β2 subunit strongly correlates with that of α1, while expression pattern of β3 subunit resembles to that of α2. Isoform γ2 is the most widely distributed isoform of γ subunit [17].…”

Section: Gabaa Receptors and Their Subunitsmentioning

confidence: 99%

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GABA Receptors: Pharmacological Potential and Pitfalls

Jembrek¹,

Vlainić

2015

CPD

115

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Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, plays a key role in the regulation of neuronal transmission throughout the brain, affecting numerous physiological and psychological processes. Changes in GABA levels provoke disbalance between excitatory and inhibitory signals, and are involved in the development of numerous neuropsychiatric disorders. GABA exerts its effects via ionotropic (GABAA) and metabotropic (GABAB) receptors. Both types of receptors are targeted by many clinically important drugs that affect GABAergic function and are widely used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, aggressive behaviour, and other pathophysiological conditions and diseases. Of particular importance are drugs that modulate GABAA receptor complex, such as benzodiazepines, barbiturates, neuroactive steroids, intravenous and inhalational anesthetics, and ethanol. Molecular interactions and subsequent pharmacological effects induced by drugs acting at GABAA receptors are extremely complex due to structural heterogeneity of GABAA receptors and existence of numerous allosterically interconnected binding sites and various chemically distinct ligands that are able to bound to them. There is a growing interest in the development and application of subtype-selective drugs that will achieve specific therapeutic benefits without undesirable side effects. The aim of this review is to briefly summarize the key pharmacological properties of GABA receptors, and to present selected novel findings with the potential to open new perspectives in the development of more effective therapeutic strategies.

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Section: Gabaa Receptors and Their Subunitsmentioning

confidence: 99%

Section: Modulation Of Gabaa Receptors By Pharmacological Agentsmentioning

confidence: 99%

Section: Modulation Of Gabaa Receptors By Pharmacological Agentsmentioning

confidence: 99%

Section: Gabaa Receptors and Their Subunitsmentioning

confidence: 99%

See 2 more Smart Citations

GABA Receptors: Pharmacological Potential and Pitfalls

Jembrek¹,

Vlainić

2015

CPD

115

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“…Moreover, the observed changes are not substantially different from those detected after prolonged exposure of these cells to high doses of the classical benzodiazepine, diazepam [14] . Despite of many studies, the molecular mechanisms involved in the development of tolerance to the actions of benzodiazepines remain unknown [15][16][17] . The aim of our study was to explore the molecular mechanisms induced by zolpidem treatment using radioligand binding assays.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

et al. 2012

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Aim: Zolpidem is a non-benzodiazepine agonist at benzodiazepine binding site in GABA A receptors, which is increasingly prescribed. Recent studies suggest that prolonged zolpidem treatment induces tolerance. The aim of this study was to explore the adaptive changes in GABA A receptors following short and long-term exposure to zolpidem in vitro. Methods: Human embryonic kidney (HEK) 293 cells stably expressing recombinant α1β2γ2s GABA A receptors were exposed to zolpidem (1 and 10 μmol/L) for short-term (2 h daily for 1, 2, or 3 consecutive days) or long-term (continuously for 48 h). Radioligand binding studies were used to determine the parameters of Conclusion:The results suggest that continuous, but not intermittent and short-term, zolpidem-exposure is able to induce adaptive changes in GABA A receptors that could be related to the development of tolerance and dependence.

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Respiratory and behavioral dysfunction following loss of the GABA_A receptor α4 subunit

et al. 2013

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γ-Aminobutyric acid type A (GABAA) receptor plasticity participates in mediating adaptation to environmental change. Previous studies in rats demonstrated that extrasynaptic GABAA receptor subunits and receptors in the pons, a brainstem region involved in respiratory control, are upregulated by exposure to sustained hypobaric hypoxia. In these animals, expression of the mRNA encoding the extrasynaptic α4 subunit rose after 3 days in sustained hypoxia, while those encoding the α6 and δ subunits increased dramatically by 2 weeks. However, the participation of extrasynaptic subunits in maintaining respiration in normoxic conditions remains unknown. To examine the importance of α4 in a normal environment, respiratory function, motor and anxiety-like behaviors, and expression of other GABAA receptor subunit mRNAs were compared in wild-type (WT) and α4 subunit-deficient mice. Loss of the α4 subunit did not impact frequency, but did lead to reduced ventilatory pattern variability. In addition, mice lacking the subunit exhibited increased anxiety-like behavior. Finally, α4 subunit loss resulted in reduced expression of other extrasynaptic (α6 and δ) subunit mRNAs in the pons without altering those encoding the most prominent synaptic subunits. These findings on subunit-deficient mice maintained in normoxia, in conjunction with earlier findings on animals maintained in chronic hypoxia, suggest that the expression and regulation of extrasynaptic GABAA receptor subunits in the pons is interdependent and that their levels influence respiratory control as well as adaptation to stress.

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Regulation of GABA_AReceptor Subunit Expression by Pharmacological Agents

Cited by 188 publications

References 281 publications

GABA Receptors: Pharmacological Potential and Pitfalls

GABA Receptors: Pharmacological Potential and Pitfalls

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

Respiratory and behavioral dysfunction following loss of the GABA_A receptor α4 subunit

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Regulation of GABAAReceptor Subunit Expression by Pharmacological Agents

Cited by 188 publications

References 281 publications

GABA Receptors: Pharmacological Potential and Pitfalls

GABA Receptors: Pharmacological Potential and Pitfalls

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

Respiratory and behavioral dysfunction following loss of the GABAA receptor α4 subunit

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Regulation of GABA_AReceptor Subunit Expression by Pharmacological Agents

Respiratory and behavioral dysfunction following loss of the GABA_A receptor α4 subunit