Effects of cimetidine-like drugs on recombinant GABAA receptors

Cannon, Keri E.; Fleck, Mark W.; Hough, Lindsay B.

doi:10.1016/j.lfs.2004.05.020

Cited by 20 publications

(10 citation statements)

References 20 publications

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“…Histamine analog H2 blockers act on heteromultimeric GABA A receptors as reported previously (23,24). Our findings may explain the molecular basis of this observed action as we found that such molecules directly act on ␤ subunits.…”

Section: Resultssupporting

confidence: 87%

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: Resultssupporting

confidence: 87%

Histamine Action on Vertebrate GABAA Receptors

Saras¹,

Gisselmann²,

Vogt-Eisele

et al. 2008

Journal of Biological Chemistry

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“…In general, H 2 antagonists are considered to be relatively safe drugs, with less than 3% of the population reporting side effects, most of which are minor (Goodman et al, 2001). In laboratory animals and/or humans, however, cimetidine can produce significant additional effects including mental confusion, seizures, antinociception, and adverse drug interactions (Goodman et al, 2001;Cannon et al, 2004). The antinociceptive and seizure-producing effects of cimetidine are actions on the brain that are not mediated by the H 2 receptor (Cannon et al, 2004).…”

mentioning

confidence: 99%

“…In laboratory animals and/or humans, however, cimetidine can produce significant additional effects including mental confusion, seizures, antinociception, and adverse drug interactions (Goodman et al, 2001;Cannon et al, 2004). The antinociceptive and seizure-producing effects of cimetidine are actions on the brain that are not mediated by the H 2 receptor (Cannon et al, 2004). Adverse drug interactions with cimetidine have been attributed to its well known ability to act as a low-potency inhibitor of the cytochrome P450 (P450) superfamily (Sorkin and Darvey, 1983).…”

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confidence: 99%

High-Affinity Binding of [³H]Cimetidine to a Heme-Containing Protein in Rat Brain

et al. 2007

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ABSTRACT:[ 3 H]Cimetidine (3HCIM) specifically binds to an unidentified site in the rat brain. Because recently described ligands for this site have pharmacological activity, 3HCIM binding was characterized. 3HCIM binding was saturable, heat-labile, and distinct from the histamine H 2 receptor. To test the hypothesis that 3HCIM binds to a cytochrome P450 (P450), the effects of nonselective and isoform-selective P450 inhibitors were studied. The heme inhibitor KCN and the nonselective P450 inhibitor metyrapone both produced complete, concentrationdependent inhibition of 3HCIM binding (K i ‫؍‬ 1.3 mM and 11.9 M, respectively).

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“…e Activation of NT 1 stimulates RVM "on" cell firing, facilitating nociception (Neubert et al, 2004) f Activation of this receptor can have opposing actions on nociceptive assays depending on agonist dose, route, CNS region and/or nociceptive test. i CC12 (up to 500 μM) did not display any GABA A agonist properties when tested exactly as described previously (Cannon et al, 2004) in HEK293 cells expressing recombinant α 1 β 2 χ 2 receptors (n=12). j Inactive as agonist, antagonist or allosteric modulator at 10 μM.…”

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confidence: 93%

CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist

Hough

Nalwalk

Phillips³

et al. 2007

Neuropharmacology

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SummaryImprogan, a chemical congener of cimetidine, is a highly effective non-opioid analgesic when injected into the CNS. Despite extensive characterization, neither the improgan receptor, nor a pharmacological antagonist of improgan has been previously described. Presently, the specific binding of 3 H-cimetidine (3HCIM) in brain fractions was used to discover 4(5)-((4-iodobenzyl) thiomethyl)-1H-imidazole, which behaved in vivo as the first improgan antagonist. The synthesis and pharmacological properties of this drug (named CC12) are described herein. In rats, CC12 (50 -500 nmol, icv) produced dose-dependent inhibition of improgan (200 -400 nmol) antinociception on the tail flick and hot plate tests. When given alone to rats, CC12 had no effects on nociceptive latencies, or on other observable behavioral or motor functions. Maximal inhibitory effects of CC12 (500 nmol) were fully surmounted with a large icv dose of improgan (800 nmol), demonstrating competitive antagonism. In mice, CC12 (200-400 nmol, icv) behaved as a partial agonist, producing incomplete improgan antagonism, but also limited antinociception when given alone. Radioligand binding, receptor autoradiography, and electrophysiology experiments showed that CC12's antagonist properties are not explained by activity at 25 sites relevant to analgesia, including known receptors for cannabinoids, opioids or histamine. The use of CC12 as an improgan antagonist will facilitate the characterization of improgan analgesia. Furthermore, because CC12 was also found presently to inhibit opioid and cannabinoid antinociception, it is suggested that this drug modifies a biochemical mechanism shared by several classes of analgesics. Elucidation of this mechanism will enhance understanding of the biochemistry of pain relief.

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Effects of cimetidine-like drugs on recombinant GABAA receptors

Cited by 20 publications

References 20 publications

Histamine Action on Vertebrate GABAA Receptors

Histamine Action on Vertebrate GABAA Receptors

High-Affinity Binding of [³H]Cimetidine to a Heme-Containing Protein in Rat Brain

CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist

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Effects of cimetidine-like drugs on recombinant GABAA receptors

Cited by 20 publications

References 20 publications

Histamine Action on Vertebrate GABAA Receptors

Histamine Action on Vertebrate GABAA Receptors

High-Affinity Binding of [3H]Cimetidine to a Heme-Containing Protein in Rat Brain

CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist

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High-Affinity Binding of [³H]Cimetidine to a Heme-Containing Protein in Rat Brain