The agonistic action of pentobarbital on GABAA β-subunit homomeric receptors

Cestari, Ismar N.; Uchida, Ichirō; Li, Li; Burt, David R.; Yang, Jay

doi:10.1097/00001756-199603220-00023

Cited by 59 publications

(53 citation statements)

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“…3-7 days after injection, histamine-and GABA-elicited currents were recorded in the voltage clamp configuration. We used the known ␤ channel agonist pentobarbital (15,16,18) as a positive control and found that 3 mM histamine could also directly open homomultimeric ␤ 3 channels with an average current amplitude of 536 nA (Ϯ95, n ϭ 15). When compared with saturating concentrations of pentobarbital, histamine evoked currents were smaller, reaching 67% (Ϯ6%, n ϭ 8, p ϭ 0.008) of the pentobarbital response (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1, B and C). It has been reported that homomultimeric ␤ channels are activated by GABA (15)(16)(17)(18). Our experiments expressing ␤ 2 or ␤ 3 confirmed the effect of GABA, but even at high, saturating GABA concentrations (3 mM), the amplitudes were only 10% of the histamine-activated currents (␤ 3 : I GABA (3 mM) / I Histamine (10 mM) ϭ 0.11 Ϯ 0.012 (n ϭ 10)).…”

Section: Resultsmentioning

confidence: 99%

“…The Action of Histamine on ␣ 1 ␤ 2 ␥ 2 Receptors-The action of histamine on the ␤ subunits resembles that of allosteric GABA A modulators such as propofol and barbiturates, which also activate currents at homomultimeric ␤ receptors directly (15,16,18). At heteromultimeric GABA A receptors, such modulators potentiate the action of GABA (25).…”

Section: Resultsmentioning

confidence: 99%

“…The mode of potentiation resembles anesthetics such as propofol; like propofol, it targets ␤ subunits and opens homomultimeric ␤ channels directly but modulates the GABA response at heteromultimeric channels (15,16,18,27,29,30). Also the influence of the ␥ 2 subunit is similar.…”

Section: Discussionmentioning

confidence: 99%

“…GABA A receptors are heteropentameric proteins constructed of various subunits (␣, ␤, ␥, ␦, , ⑀, and ). The most prominent native receptors are heteromultimers of ␣, ␤, and ␥ subunits (14), but at least in recombinant systems, functional homomultimeric receptors composed of ␤ or ␥ subunits alone exist (15)(16)(17)(18)(19). Such homomultimeric ion channels differ in many aspects from the conventional, heteromultimeric GABA A receptors and were therefore candidates for receptors with unexpected new properties.…”

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Histamine Action on Vertebrate GABAA Receptors

Saras¹,

Gisselmann²,

Vogt-Eisele

et al. 2008

Journal of Biological Chemistry

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Histamine is not only a crucial cytokine in the periphery but also an important neurotransmitter and neuromodulator in the brain. It is known to act on metabotropic H1-H4 receptors, but the existence of directly histamine-gated chloride channels in mammals has been suspected for many years. However, the molecular basis of such mammalian channels remained elusive, whereas in invertebrates, genes for histamine-gated channels have been already identified. In this report, we demonstrated that histamine can directly open vertebrate ion channels and identified ␤ subunits of GABA A receptors as potential candidates for histamine-gated channels. In Xenopus oocytes expressing homomultimeric ␤ channels, histamine evoked currents with an EC 50 of 212 M (␤ 2 ) and 174 M (␤ 3 ), whereas GABA is only a very weak partial agonist. We tested several known agonists and antagonists for the histamine-binding site of H1-H4 receptors and described for ␤ channels a unique pharmacological profile distinct from either of these receptors. In heteromultimeric channels composed of ␣ 1 ␤ 2 or ␣ 1 ␤ 2 ␥ 2 subunits, we found that histamine is a modulator of the GABA response rather than an agonist as it potentiates GABA-evoked currents in a ␥ 2 subunit-controlled manner. Despite the vast number of synthetic modulators of GABA A receptors widely used in medicine, which act on several distinct sites, only a few endogenous modulators have yet been identified. We show here for the first time that histamine modulates heteromultimeric GABA A receptors and may thus represent an endogenous ligand for an allosteric site.Ligand-gated ion channels mediate the fast responses of cells to neurotransmitters (1). A universal feature of ligand-gated ion channels subunits is a common topology, comprising four membrane-spanning segments (M1-M4) and a huge N-terminal extracellular domain with a hyperconserved cysteine loop motif. In vertebrates, this "Cys loop" family of phylogenetically related genes codes for anion and cation channels activated by acetylcholine and serotonin (cation channels) or GABA 3 and glycine (anion channels) (1, 2). Despite the many years of intensive research on such ion channels, recent reports revealed unexpected new findings about this channel family. In vertebrates, a gene for zinc-gated ion channels was recently discovered (3). In insects, new classes of ligand-gated chloride channels gated by histamine or pH and cation channels gated by GABA were reported (4 -7

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Histamine Action on Vertebrate GABAA Receptors

Saras¹,

Gisselmann²,

Vogt-Eisele

et al. 2008

Journal of Biological Chemistry

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GABAA receptor in growth cones: The outline of GABAA receptor-dependent signaling in growth cones is applicable to a varitey of α-subunit species

et al. 1999

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The growth cone is responsible for axonal elongation and pathfinding by responding to various modulators for neurite growth, including neurotransmitters. We demonstrated an outline of the gamma aminobutyric acid (GABA)(A)-dependent signaling in growth cones. Here, we examined the effects of the modulators of GABA(A) receptor on the signaling in growth cones. Phenobarbital or propofol, acting on beta-subunit, enhanced the [Cl(-)]infi change and [Ca(2+)](i) elevation by the GABA stimulation to isolated growth cones. Besides, propofol enhanced GABA-dependent phosphorylation of growth-associated protein of 43 kDa (GAP-43) by protein kinase C. In contrast, an alpha-subunit acting agent diazepam did not modulate any of the above signals. Next, we examined the effect of the developmental change of alpha-subunit on the outline of the GABA(A)-dependent signaling in growth cones. We also found that the amounts of several different alpha-subunit isoforms developmentally increased or decreased in growth cone membrane (GCM), but that the affinity and density of the [(3)H]diazepam binding sites were similar to those in adult synaptic membrane. Taken together, our results strongly suggest that each step of GABA(A)-dependent signaling in GCM is not modified by diazepam, indicating that the signaling pathway mediated by GABA(A) receptor in growth cones is applicable to any compositional change of alpha-subunit isoforms.

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