Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response

Mancama, D; Arranz, Maria; Munro, Janet; Osborne, Sarah; Makoff, Andrew; Collier, David; Kerwin, Robert

doi:10.1016/s0304-3940(02)00178-7

Cited by 59 publications

(37 citation statements)

References 18 publications

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“…Another ECS SNP identified in the histamine H 1 receptor (L449S corresponding to V329 in TMH7 of the hamster a 1B -AR) was suspected of being involved in asthma. However, no correlation to asthma was identified (Mancama et al, 2002), which is consistent with the lack of effect of the V329A mutation on a 1B -AR function.…”

Section: Discussionsupporting

confidence: 62%

Extracellular Surface Residues of theα_1B-Adrenoceptor Critical for G Protein–Coupled Receptor Function

et al. 2014

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Ligand binding and conformational changes that accompany signaling from G protein-coupled receptors (GPCRs) have mostly focused on the role of transmembrane helices and intracellular loop regions. However, recent studies, including several GPCRs cocrystallized with bound ligands, suggest that the extracellular surface (ECS) of GPCRs plays an important role in ligand recognition, selectivity, and binding, as well as potentially contributing to receptor activation and signaling. This study applied alanine-scanning mutagenesis to investigate the role of the complete ECS of the a 1B -adrenoreceptor on norepinephrine (NE) potency, affinity, and efficacy. Half (24 of 48) of the ECS mutations significantly decreased NE potency in an inositol 1-phosphate assay. Most mutations reduced NE affinity (17) determined from [ 3 H]prazosin displacement studies, whereas four mutations at the entrance to the NE binding pocket enhanced NE affinity. Removing the influence of NE affinity and receptor expression levels on NE potency gave a measure of NE efficacy, which was significantly decreased for 11 of 48 ECS mutants. These different effects tended to cluster to different regions of the ECS, which is consistent with different regions of the ECS playing discrete functional roles. Exposed ECS residues at the entrance to the NE binding pocket mostly affected NE affinity, whereas buried or structurally significant residues mostly affected NE efficacy. The broad potential for ECS mutations to affect GPCR function has relevance for the increasing number of nonsynonymous single nucleotide polymorphisms now being identified in GPCRs.

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Section: Discussionsupporting

confidence: 62%

Extracellular Surface Residues of theα_1B-Adrenoceptor Critical for G Protein–Coupled Receptor Function

et al. 2014

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“…However, no clear evidence of their role on treatment response has been obtained. 114,132 Targeting of muscarinic receptors has been suggested to contribute to the beneficial actions of clozapine, as suggested by in vitro studies. 187,188 Marginal associations detected in our laboratory (Dalu Mancama, Institute of Psychiatry, London, UK, personal communication) agree with this assumption.…”

Section: Pharmacodynamic Factorsmentioning

confidence: 99%

“…Individual association studies had identified several variants in clozapinetargeted receptor with influence on clinical outcome. 114,121,126,129,199 We combined information of genetic variants associated with response and developed an algorithm for the prediction of clozapine outcome. A combination of variants in the genes coding for 5-HT 2A , 5-HT 2C , H 2 receptors and for the serotonin transporter 5-HTT resulted in the correct prediction of response in 76% of cases.…”

Section: Prediction Of General Responsementioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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“…45 In contrast, the adrenoreceptor alpha 2A (ADRA2A), 129,130 brain-derived neurotrophic factor (BDNF), 131 human glutathione peroxidase (GPX1), 132 glutamate receptor ionotropic N-methyl D-aspartate 1 (GRIN1), 106 2A (GRIN2A) 106 and 2B (GRIN2B), 106,133 histamine receptor H1 (HRH1), 134 histamine receptor H2 (HRH2), 134 and superoxide dismutase 2 mitochondrial (MNSOD) 132 were investigated and no significant associations were observed. The tumor necrosis factor gene (TNF) showed significant 49 and nonsignificant 135 results.…”

Section: -98mentioning

confidence: 99%

Pharmacogenetics in schizophrenia: a review of clozapine studies

Kohlrausch

2013

Rev. Bras. Psiquiatr.

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Objectives: Clozapine is quite effective to treat schizophrenia, but its use is complicated by several factors. Although many patients respond to antipsychotic therapy, about 50% of them exhibit inadequate response, and ineffective medication trials may entail weeks of unremitted illness, potential adverse drug reactions, and treatment nonadherence. This review of the literature sought to describe the main pharmacogenetic studies of clozapine and the genes that potentially influence response to treatment with this medication in schizophrenics. Methods: We searched the PubMed database for studies published in English in the last 20 years using keywords related to the topic. Results and Conclusions: Our search yielded 145 studies that met the search and selection criteria. Of these, 21 review articles were excluded. The 124 studies included for analysis showed controversial results. Therefore, efforts to identify key gene mechanisms that will be useful in predicting clozapine response and side effects have not been fully successful. Further studies with new analysis approaches and larger sample sizes are still required.

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Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response

Cited by 59 publications

References 18 publications

Extracellular Surface Residues of theα_1B-Adrenoceptor Critical for G Protein–Coupled Receptor Function

Extracellular Surface Residues of theα_1B-Adrenoceptor Critical for G Protein–Coupled Receptor Function

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Pharmacogenetics in schizophrenia: a review of clozapine studies

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Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response

Cited by 59 publications

References 18 publications

Extracellular Surface Residues of theα1B-Adrenoceptor Critical for G Protein–Coupled Receptor Function

Extracellular Surface Residues of theα1B-Adrenoceptor Critical for G Protein–Coupled Receptor Function

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Pharmacogenetics in schizophrenia: a review of clozapine studies

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Product

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Extracellular Surface Residues of theα_1B-Adrenoceptor Critical for G Protein–Coupled Receptor Function

Extracellular Surface Residues of theα_1B-Adrenoceptor Critical for G Protein–Coupled Receptor Function