Structural change in dopamine D<sub>2</sub> receptor gene in a patient with neuroleptic malignant syndrome

Ram, Alpana; Cao, Qiuhe; Keck, Paul E.; Pope, Harrison G.; Otani, Koichi; Addonizio, Gerard; McElroy, Susan L.; Kaneko, Sunao; Redlichova, Michaela; Gershon, Elliot S.; Gejman, Pablo V.

doi:10.1002/ajmg.1320600311

Cited by 30 publications

(8 citation statements)

References 22 publications

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“…Missense Variants in the hD1R but not the hD2R Exhibit Decreased Basal and Dopamine Stimulated Signaling A review of the literature (Itokawa et al 1993;Ram et al 1995) and the SNP database (http://www.ncbi.nlm.nih.gov/ projects/SNP) revealed the presence of five and three nonsynonymous single amino acid substitutions in the hD1R and the hD2R, respectively. In the hD1R, the missense variants were found to reside in either the first transmembrane domain, the fifth transmembrane domain, or in the third intracellular loop (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Pharmacological Analysis of Human D1 and D2 Dopamine Receptor Missense Variants

et al. 2008

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Drugs targeting dopamine receptors have been the focus of much research over the past 30 years, in large part because of their role in treating multiple pathological conditions including Parkinson's disease, schizophrenia, Tourette's syndrome, and hyperprolactinemia. Missense mutations in G protein-coupled receptors (GPCRs) can alter basal and/or ligand-induced signaling, which in turn can affect individuals' susceptibility to disease and/or response to therapeutics. To date, five coding variants in the human D1 receptor (hD1R; T37P, T37R, R50S, S199A, and A229T) and three in the human D2 receptor (hD2R; P310S, S311C, and T351A) have been reported in the NCBI single nucleotide polymorphism database. We utilized site-directed mutagenesis to generate cDNAs encoding these receptor isoforms. After expression in either HEK293 or neuronal GT1 cells, basal and ligand-induced signaling of each of these receptors was determined and compared to wild type. In addition, we investigated expression levels of each recombinant receptor and the effect of inverse agonist administration. Our data demonstrate that naturally occurring amino acid substitutions in the hD1R can lead to alterations in expression levels as well as in basal and ligand-induced signaling. The potency and efficacy of dopamine, synthetic agonists (i.e., fenoldopam, SKF-38393, SKF-82958, and SCH23390), and inverse agonists [i.e., flupenthixol and (+)butaclamol] were reduced at selected hD1R variants. Furthermore, inverse agonist induced effects on expression levels were sensitive to selected amino acid substitutions. In contrast to the hD1R variants, hD2R polymorphisms did not affect ligand function or receptor expression. The observation that the hD1R mutations induce significant alterations in pharmacologic properties may have implications both for disease susceptibility and/or therapeutic response to dopaminergic ligands.

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Section: Resultsmentioning

confidence: 99%

Pharmacological Analysis of Human D1 and D2 Dopamine Receptor Missense Variants

et al. 2008

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“…Vulnerability may be related to variations in the genes for neurotransmitter receptors or metabolic activity. NMS in patients with mutations in the debrisoquine 4‐hydroxylase (55) and dopamine D 2 receptor (56) genes provide evidence for genetic involvement. Suzuki et al (57) examined the association between NMS and the Taql A polymorphism of the dopamine D 2 receptor (DRD 2 ) gene, which alters DRD 2 density and function.…”

Section: Risk Factorsmentioning

confidence: 99%

Neuroleptic malignant syndrome: risk factors, pathophysiology, and treatment

Ananth

Aduri

Parameswaran

et al. 2004

Acta Neuropsychiatr.

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Neuroleptic malignant syndrome (NMS) is associated with the administration of antipsychotic agents and other drugs such as l-dopa, antidepressants, and antihistaminic agents. Unexpected changes in mental status, new-onset catatonia, episodic tachycardia, tachypnea, hypertension, dysarthria, dysphagia, diaphoresis, sialorrhea, incontinence, low-grade temperature elevations, and rigidity should arouse suspicion. Several lines of evidence provide support for the involvement of dopamine. Most of the drugs implicated in NMS are D2 dopamine receptor antagonists. Central noradrenergic activity is also possibly related to the disorder, as sympathetic hyperactivity is associated with the active phase of NMS. Currently, the definitive role of GABA deficiency in NMS is yet to be established. Differential diagnosis should include malignant hyperthermia, lethal catatonia, lithium toxicity, serotonin syndrome, and heat stroke. A high degree of suspicion and the discontinuation of antipsychotic agents even if the diagnosis is not established are essential for the safety of the patient. Treatment of NMS should be individualized and be based empirically on the character, duration, and severity of the clinical signs and symptoms noted. The initial step in the treatment of NMS is the removal of the offending agent. Full-blown NMS is a serious condition and requires immediate supportive, nutritive, and electrolyte therapies. The administration of drugs that can improve NMS, such as IV dantrolene and/or oral bromocriptine, may also be taken into consideration, based on the severity and nature of the NMS.

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“…For example, asthmatic patients who are homozygous for a mutation in the ␤ 2 adrenergic receptor were found to be more likely to be steroid-dependent (35). In addition, the Ser 310 variant of DRD2 was found in a patient with a clinical history of neuroleptic malignant syndrome (NMS) (8), and a larger series of patients with NMS is being investigated to establish whether this allele is associated with an increased susceptibility to NMS. Mutations in G protein-coupled receptors do not necessarily produce clinical pathology, e.g.…”

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confidence: 99%

Functional Analysis of the Human D2 Dopamine Receptor Missense Variants

Cravchik¹,

Sibley

Gejman³

1996

Journal of Biological Chemistry

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119

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Further diversity in the human dopamine receptors can be achieved by alternative RNA splicing and by the existence of expressed polymorphic sequences (1-3). For instance, the DRD2 gene can generate two alternative RNA splicing isoforms, D 2L (long) and D 2S (short), that differ by the presence or absence of a 29-amino acid sequence in the third cytoplasmic loop of the receptor protein (4, 5). The human DRD2 gene also has three identified DNA variants, which predict the amino acid substitutions Val 96 3 Ala, Pro 310 3 Ser, and Ser 311 3 Cys in the receptor protein (6). The prevalence of these DRD2 variants varies greatly in different human populations; in the Pima Native American population, the prevalence of the Cys 311

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Structural change in dopamine D₂ receptor gene in a patient with neuroleptic malignant syndrome

Cited by 30 publications

References 22 publications

Pharmacological Analysis of Human D1 and D2 Dopamine Receptor Missense Variants

Pharmacological Analysis of Human D1 and D2 Dopamine Receptor Missense Variants

Neuroleptic malignant syndrome: risk factors, pathophysiology, and treatment

Functional Analysis of the Human D2 Dopamine Receptor Missense Variants

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Structural change in dopamine D2 receptor gene in a patient with neuroleptic malignant syndrome

Cited by 30 publications

References 22 publications

Pharmacological Analysis of Human D1 and D2 Dopamine Receptor Missense Variants

Pharmacological Analysis of Human D1 and D2 Dopamine Receptor Missense Variants

Neuroleptic malignant syndrome: risk factors, pathophysiology, and treatment

Functional Analysis of the Human D2 Dopamine Receptor Missense Variants

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Structural change in dopamine D₂ receptor gene in a patient with neuroleptic malignant syndrome