Differential benzodiazepine pharmacology of mammalian recombinant GABAA receptors

Blankenfeld, G. von; Ymer, Sanie; Pritchett, Dolan B.; Sontheimer, Harald; Ewert, Markus; Seeburg, Peter H.; Kettenmann, Helmut

doi:10.1016/0304-3940(90)90467-n

Cited by 79 publications

(37 citation statements)

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“…Decreases in ␥2 subunit transcript levels of the kind reported here and marked decreases in benzodiazepine binding (17) indicate that a major component of the cortical inhibitory neurotransmitter system is affected in schizophrenics. Because ␥2 subunits are essential for high-affinity benzodiazepine binding (22,(25)(26)(27)(28)(29)(30)(31)45), especially for binding of flunitrazepam (18,28), reduction in ␥2 protein resulting from reduced transcript levels provides a basis for the decrease in The ␥2 subunit is one of the most highly expressed and widely distributed GABA A receptor subunits in the mammalian central nervous system, including the developing and adult cerebral cortex (19-21, 24, 25, 46-49). It is normally colocalized with two other highly expressed subunits, ␣1 and ␤2 (20,21,24), suggesting that ␥2, along with ␣1 and ␤2 subunits are fundamental components of the major subtype of GABA A receptors in the mammalian brain (19-21, 45, 47, 50).…”

Section: Discussionmentioning

confidence: 99%

“…␥2 subunits, along with ␣1 and ␤2 subunits, are the principal contributors to most native GABA A receptors (19)(20)(21)(22)(23), including in the primate cerebral cortex (24). ␣-Subunits are necessary for selectivity of the receptor for benzodiazepines (25), whereas the ␥2 subunit is essential for high-affinity benzodiazepine binding (18,(25)(26)(27)(28)(29)(30)(31). ␥2 subunits exist in two isoforms, products of alternative mRNA splicing: short (␥2S) and long (␥2L), the latter having an 8-aa insert (32,33).…”

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confidence: 99%

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Altered ratios of alternatively spliced long and short γ2 subunit mRNAs of the γ-amino butyrate type A receptor in prefrontal cortex of schizophrenics

Huntsman

Tran²,

Potkin³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

126

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The relative abundance of alternatively spliced long (␥2L) and short (␥2S) mRNAs of the ␥2 subunit of the ␥-amino butyrate type A (GABA A ) receptor was examined in dorsolateral prefrontal cortex of schizophrenics and matched controls by using in situ hybridization histochemistry and semiquantitative reverse transcription-PCR (RT-PCR) amplification. A cRNA probe identifying both mRNAs showed that the transcripts are normally expressed at moderately high levels in the prefrontal cortex. Consistent with previous studies, overall levels of ␥2 transcripts in prefrontal cortex of brains from schizophrenics were reduced by 28.0%, although this reduction did not reach statistical significance. RT-PCR, performed under nonsaturating conditions on total RNA from the same blocks of tissue used for in situ hybridization histochemistry, revealed a marked reduction in the relative proportion of ␥2S transcripts in schizophrenic brains compared with controls. In schizophrenics, ␥2S transcripts had fallen to 51.7% (؎7.9% SE; P < 0.0001) relative to control levels. Levels of ␥2L transcripts showed only a small and nonsignificant reduction of 16.9% (؎12.0% SE, P > 0.05). These findings indicate differential transcriptional regulation of two functionally distinct isoforms of one of the major GABA A receptor subunits in the prefrontal cortex of schizophrenics. The specific reduction in relative abundance of ␥2S mRNAs and the associated relative increase in ␥2L mRNAs should result in functionally less active GABA A receptors and have severe consequences for cortical integrative function.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Altered ratios of alternatively spliced long and short γ2 subunit mRNAs of the γ-amino butyrate type A receptor in prefrontal cortex of schizophrenics

Huntsman

Tran²,

Potkin³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

126

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“…The benzodiazepine sensitivity of GABA, receptors differs when different a subtypes are combined with p-and y-subunits (Table 2) (12)(13)(14)(15)(16). The alpy-subunits produce diazepam-and zolpidem-sensitive BZ 1 GABA, receptors, a 2 p y -and a3py-subunits produce BZ2a,b GABA, receptors with high diazepam and low zolpidem sensitivity, &Spy-subunits produce BZ2c GABA, receptors with high diazepam sensitivity but zolpidem insensitivity, and 014-or a6py-subunits produce BZ3 GABA, receptors that are benzodiazepine insensitive.…”

Section: Pharmacology Of Recombinant Gabaa Receptorsmentioning

confidence: 99%

“…The distribution of mRNAs in the CNS determined by in situ hybridization is very different for each subunit subtype. For example, the p-subunit is expressed primarily in the retina (17), whereas various a, p, and y subtypes and the single 6 subtype show very different regional as well as developmental distributions (1 [8][9][10][11][12][13][14][15][16][17][18][19][20]. Immunoprecipitation studies have shown that different specific combinations of GABA, receptor-subtypes occur in the different regions of the brain.…”

Section: Pharmacology Of Recombinant Gabaa Receptorsmentioning

confidence: 99%

Acute Cellular Alterations in the Hippocampus After Status Epilepticus

Macdonald

Kapur

1999

Epilepsia

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Summary: The critical, fundamental mechanisms that determine the emergence of status epilepticus from a single seizure and the prolonged duration of status epilepticus are uncertain. However, several general concepts of the pathophysiology of status epilepticus have emerged: (a) the hippocampus is consistently activated during status epilepticus; (b) loss of GABA‐mediated inhibitory synaptic transmission in the hippocampus is critical for emergence of status epilepticus; and, finally (c) glutamatergic excitatory synaptic transmission is important in sustaining status epilepticus. This review focuses on the alteration of GABAergic inhibition in the hippocampus that occurs during the prolonged seizures of status epilepticus. If reduction in GABAergic inhibition leads to development of status epilepticus, enhancement of GABAergic inhibition would be expected to interrupt status epilepticus. Benzodiazepines and barbiturates are both used in the treatment of status epilepticus and both drugs enhance GABAA receptor‐mediated inhibition. However, patients often become refractory to benzodiazepines when seizures are prolonged, and barbiturates are often then used for these refractory cases of status epilepticus. Recent evidence suggests the presence of multiple GABAA receptor isoforms in the hippocampus with different sensitivity to benzodiazepines but similar sensitivity to barbiturates, thus explaining why the two drug classes might have different clinical effects. In addition, rapid functional plasticity of GABAA receptors has been demonstrated to occur during status epilepticus in rats. During status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. The loss of sensitivity of the animals to diazepam during status epilepticus was accompanied by an alteration in the functional properties of hippocampal dentate granule cell GABAA receptors. Dentate granule cell GABAA receptor currents from rats undergoing status epilepticus had reduced sensitivity to diazepam and zinc but normal sensitivity to GABA and pentobarbital. Therefore, the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABAA receptors, possibly explaining why benzodiazepines and barbiturates may not be equally effective during treatment of the prolonged seizures of status epilepticus. A comprehensive understanding of the cellular and molecular events leading to the development, maintenance, and cytotoxicity of status epilepticus should permit development of more effective treatment strategies and reduction in the mortality and morbidity of status epilepticus.

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“…It has also been reported that differing 7-subunits confer various sensitivities to benzodiazepines influencing both the affinity and efficacy of various benzodiazepine site ligands as functional modulators of GABAA receptors. Benzodiazepines potentiated GABA effects on receptor complexes containing T2 subunits much greater than these containing T1 subunits [30,31]. Moreover, fl-carbolines such as methyl-6,7-dimethoxy-4-ethyl-fl-carboline-3-carboxylate (DMCM) and methyl-fl-carboline-3-carboxylate (fl-CCM) act as negative GABAA receptor modulators in recombinants containing ~1(~2) fll and 72 subunits but act as positive modulators at 0flfll?l and ~2fll?l receptors [32].…”

Section: I Imentioning

confidence: 99%

Identification of the GABA_A receptor subtype mRNA in human pancreatic tissue

Wu¹,

Reyes²,

Lan³

1994

FEBS Letters

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Evidence suggests a physiological role of the GABA^ receptor in the pancreas. Clinically, an autoimmune reaction involving the GABA biosynthesizing enzyme, glutamic acid decarboxylase has been implicated in the development of insulin-dependent diabetes mettitus. To determine the subtypes of GABA^ receptor expressed in human pancreas, we analyzed, with the use of the reverse-transcription/polymerase chain reaction technique human pancreatic tissue for the presence of GABAA receptor subunits ~1-6, ]/1-3, and 7/1-2 transcripts. Unlike brain tissue, pancreatic tissue only expresses the cz2, ]/3 and 7'1 subunits. Our results provide evidence of a specific GABAA receptor subtype expressed in human pancreatic tissue.Key words." GABA; Human pancreas; GABAA receptor; Subunit ~u~on~,-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the vertebrate central nervous system (CNS). It mediates its inhibitory action through a receptor complex, GABAA, that is a hetero-oligomeric protein composed of several distinct polypeptide subunits [1]. In addition to GABA binding sites, the GABAA receptor also contains several independent modulatory sites for therapeutic useful drugs such as benzodiazepines, barbiturates and neuroactive steroids [2,3]. Molecular cloning has identified at least 16 GABAA receptor subunits that can be grouped into several families (~-, fl-,7-,tL and p-) [4,5]. Functional expression of these subunits in mammalian cell lines or Xenopus oocyte results in GABAA receptors with differential pharmacological characteristics [6,7]. The multiplicity of GABAA receptors expressed in the CNS provides one explanation for the complex pharmacology observed in brain homogenate [8,9].In addition to the important role that GABA plays in the brain, the presence of GABA in nonneuronal organs has been demonstrated [10,11]. This suggests the involvement of GABA in the physiological functions of these nonneuronal tissues. However, the concentrations of GABA in these tissues are generally low, about 1% of that in brain, with the exception of the female genital tract [12] and pancreatic islets [13]. In pancreatic islets, the GABA concentration is comparable to that of the CNS [14], however, it is still unclear why such a high concentration of GABA exists in the endocrine pancreas. In situ studies of GABA regulation of pancreatic hormone release have been controversial [15,16]. Recently though, the function and characterization of the GABA system in the pancreas has become a focus of interest as glutamic acid decarboxylase, a GABA biosynthesizing enzyme, is a dominant autoantigen in insulindependent diabetes mellitus [17]. This 65 kDa pancreatic fl cell protein is a target of an autoimmune response in patients with this disease [18]. In pancreatic islet, evidence suggests GABA and insulin co-secretion from fl cell, but no GABA receptors were detected by [3H]-GABA binding in the fl cells [11]. A recent electrophysiological study revealed a GABA-triggered inhibitory hyperpolarization and cessation of spiking act...

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Differential benzodiazepine pharmacology of mammalian recombinant GABAA receptors

Cited by 79 publications

References 10 publications

Altered ratios of alternatively spliced long and short γ2 subunit mRNAs of the γ-amino butyrate type A receptor in prefrontal cortex of schizophrenics

Altered ratios of alternatively spliced long and short γ2 subunit mRNAs of the γ-amino butyrate type A receptor in prefrontal cortex of schizophrenics

Acute Cellular Alterations in the Hippocampus After Status Epilepticus

Identification of the GABA_A receptor subtype mRNA in human pancreatic tissue

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Differential benzodiazepine pharmacology of mammalian recombinant GABAA receptors

Cited by 79 publications

References 10 publications

Altered ratios of alternatively spliced long and short γ2 subunit mRNAs of the γ-amino butyrate type A receptor in prefrontal cortex of schizophrenics

Altered ratios of alternatively spliced long and short γ2 subunit mRNAs of the γ-amino butyrate type A receptor in prefrontal cortex of schizophrenics

Acute Cellular Alterations in the Hippocampus After Status Epilepticus

Identification of the GABAA receptor subtype mRNA in human pancreatic tissue

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Product

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Identification of the GABA_A receptor subtype mRNA in human pancreatic tissue