AF150(S) and AF267B

Fisher, Abraham; Brandeis, Rachel; Bar-Ner, Rachel Haring Nira; Kliger-Spatz, Michal; Natan, Niva; Sonego, Hagar; Marcovitch, Itzhak; Pittel, Zipora

doi:10.1007/s12031-002-0025-3

Cited by 83 publications

(38 citation statements)

References 35 publications

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“…Furthermore, we investigated the role of other basic residues located in TM2-3L of the ␤ 2 subunit (Arg 269 and Lys 279 ) and found that only the basic residue at position 274 is sensitive to a charge reversal mutation, suggesting that it is uniquely involved in electrostatic interactions important for receptor activation. This study also confirms the importance of TM2-3L of the GABA A -R ␤ 2 subunit in receptor activation, as previously reported for the ␣ 1 , ␣ 2 , ␤ 2 , and ␤ 3 subunits (12,14,18,25). An interesting difference between the ␣ 1 and ␤ 2 subunits was observed here because ␤ 2 (L272A) failed to alter receptor function, whereas the ␣ 1 ortholog (L277A) reduces GABA sensitivity dramatically (EC 50 ϭ 278 M) (26).…”

Section: Characterization Of Mutations In Loops 2 and 7 Of Thesupporting

confidence: 92%

Charged Residues in the β2 Subunit Involved in GABAA Receptor Activation

Kash¹,

Dizon

Trudell

et al. 2004

Journal of Biological Chemistry

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Fast synaptic inhibition in the mammalian central nervous system is mediated primarily via activation of the ␥-aminobutyric acid type A receptor (GABA A -R). Upon agonist binding, the receptor undergoes a structural transition from the closed to the open state. This transition, known as gating, is thought to be associated with a sequence of conformational changes originating at the agonist-binding site, ultimately resulting in opening of the channel. Using site-directed mutagenesis and several different GABA A -R agonists, we identified a number of highly conserved charged residues in the GABA A -R ␤ 2 subunit that appear to be involved in receptor activation. We then used charge reversal double mutants and disulfide trapping to investigate the interactions between these flexible loops within the ␤ 2 subunit. The results suggest that interactions between an acidic residue in loop 7 (Asp 146 ) and a basic residue in pretransmembrane domain-1 (Lys 215 ) are involved in coupling agonist binding to channel gating.Fast synaptic inhibition is a major determinant of network dynamics in the central nervous system (1). In the mammalian brain, this is mediated primarily via activation of the ␥-aminobutyric acid type A receptor (GABA A -R) 1 (2, 3). Each GABA A -R is composed of five subunits arranged around a central ion-conducting pore (4), with each subunit consisting of a large intracellular domain, four transmembrane domains (TM1-TM4), and a larger N-terminal extracellular domain (2). Experimental evidence suggests that the GABA-binding site lies within an asymmetric pocket formed at the interface between the ␣ and ␤ receptor subunits (5-8). The channel "gate" in the GABA A -R is believed to be formed by charged residues in the TM1-TM2 loop (9 -11). The binding of agonist triggers a complex structural transition that results in the opening of the gate, allowing ions to flow through the channel. The mechanisms by which this occurs remain poorly defined.The nature of the coupling between binding and channel opening in this receptor family has been recently investigated in several laboratories. Interactions between charged residues in the flexible loops 2 and 7 in the extracellular domain and those in the short linker between the second and third transmembrane domains (TM2-3L) of the GABA A -R ␣ 1 subunit have been implicated in the process of receptor activation (12). In addition, a recent report suggests that the pre-TM1 region is critical for receptor activation in the closely related serotonin (5-HT 3 ) receptor (13). In this study, we used site-directed mutagenesis and a number of GABA A -R agonists of varying efficacies to examine the contribution of the corresponding flexible loops in the GABA A -R ␤ 2 subunit to receptor activation. Based on previous studies (12-14) and the presence of highly conserved charged residues (see Fig. 1), we hypothesized that interactions between charged residues in these domains are crucial for coupling agonist binding to channel gating. We tested this hypothesis using a charge revers...

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Section: Characterization Of Mutations In Loops 2 and 7 Of Thesupporting

confidence: 92%

Charged Residues in the β2 Subunit Involved in GABAA Receptor Activation

Kash¹,

Dizon

Trudell

et al. 2004

Journal of Biological Chemistry

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“…The M1 mAChR agonists xanomeline and AF267B (Fisher et al , 2002;Caccamo et al , 2006) were synthesized in the laboratory of Medicinal Chemistry at the Feinstein Institute for Medical Research by following previously published methodology (Supplementary Figures 1 and 2) and oxalate salt forms of the compounds were used in experiments. Atropine sulfate and atropine methyl nitrate were purchased from Sigma.…”

Section: Methodsmentioning

confidence: 99%

Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation

Rosas-Ballina

Valdés‐Ferrer

Dancho

et al. 2015

Brain, Behavior, and Immunity

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Inflammatory conditions characterized by excessive immune cell activation and cytokine release, are associated with bidirectional immune system-brain communication, underlying sickness behavior and other physiological responses. The vagus nerve has an important role in this communication by conveying sensory information to the brain, and brain-derived immunoregulatory signals that suppress peripheral cytokine levels and inflammation. Brain muscarinic acetylcholine receptor (mAChR)-mediated cholinergic signaling has been implicated in this regulation. However, the possibility of controlling inflammation by peripheral administration of centrally-acting mAChR agonists is unexplored. To provide insight we used the centrally-acting M1 mAChR agonist xanomeline, previously developed in the context of Alzheimer’s disease and schizophrenia. Intraperitoneal administration of xanomeline significantly suppressed serum and splenic TNF levels, alleviated sickness behavior, and increased survival during lethal murine endotoxemia. The anti-inflammatory effects of xanomeline were brain mAChR-mediated and required intact vagus nerve and splenic nerve signaling. The anti-inflammatory efficacy of xanomeline was retained for at least 20h, associated with alterations in splenic lymphocyte, and dendritic cell proportions, and decreased splenocyte responsiveness to endotoxin. These results highlight an important role of the M1 mAChR in a neural circuitry to spleen in which brain cholinergic activation lowers peripheral pro-inflammatory cytokines to levels favoring survival. The therapeutic efficacy of xanomeline was also manifested by significantly improved survival in preclinical settings of severe sepsis. These findings are of interest for strategizing novel therapeutic approaches in inflammatory diseases.

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“…M1 receptor agonists (AF102B, AF150(S) and AF267B-1) which increase synaptic ACh levels are related to improved cognition in various animal Alzheimer's disease models (Fisher et al 2002) and antagonists of presynaptic M2 receptors (which decrease ACh) enhance cognitive ability in rodents and non-human primates (Carey et al 2001). CHRM2 has been shown to be involved in long-term potentiation (Calabresi et al 1998), which is thought to be a fundamental mechanism in learning and memory (Silva 2003), and single nucleotide polymorphisms (SNPs) have been associated with visual evoked brain oscillations suggesting at least a role for CHRM2 in higher mental functioning in humans (Jones et al 2006), although reports that CHRM2 polymorphisms are associated with alcoholism and depression (Comings et al 2002;Edenberg and Foroud 2006;Luo et al 2005;Wang et al 2004) suggest a nonspecific phenotype.…”

Section: Introductionmentioning

confidence: 99%

No Association Between Cholinergic Muscarinic Receptor 2 (CHRM2) Genetic Variation and Cognitive Abilities in Three Independent Samples

Lind¹,

Luciano

Horan

et al. 2009

Behav Genet

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Cognitive ability has a substantial genetic component and more than 15 candidate genes have been identified over the past 8 years. One gene that has been associated with general cognitive ability is the cholinergic muscarinic 2 receptor (CHRM2). In an attempt to replicate this finding we typed marker rs8191992 (the originally reported CHRM2 SNP) in two population based cohorts-one Scottish aged over 50 years (N = 2,091) and the other English comprising non-demented elderly participants (N = 758)-and a family-based Australian adolescent sample (N = 1,537). An additional 29 SNPs in CHRM2 were typed in the Australian sample and a further seven in the English cohort. No significant association was found between CHRM2 and diverse measures of cognitive ability in any of the samples. In conclusion, this study does not support a role for CHRM2 in cognitive ability.

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AF150(S) and AF267B

Cited by 83 publications

References 35 publications

Charged Residues in the β2 Subunit Involved in GABAA Receptor Activation

Charged Residues in the β2 Subunit Involved in GABAA Receptor Activation

Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation

No Association Between Cholinergic Muscarinic Receptor 2 (CHRM2) Genetic Variation and Cognitive Abilities in Three Independent Samples

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