Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications

Abstract

The norepinephrine transporter (NET) has a major role in terminating the neurochemical signal established by the neurotransmitter norepinephrine (NE) in the synaptic cleft. The NET is also the initial site of action for therapeutic antidepressants, and drugs such as cocaine and amphetamines. Polymorphisms in the NET gene have been identified, and associations with several disorders such as depression have been proposed but not established. However, evidence of a direct association between a genetic mutation of the NET and an autonomic clinical syndrome has recently emerged. A patient and her identical twin were evaluated for typical symptoms of orthostatic intolerance (OI), a disorder mainly characterised by elevated heart rate on standing, and both were found to have clinical and laboratory signs of abnormal uptake of NE. Sequence analysis of the patients' NET gene identified a mutation that resulted in more than 98% loss of function as compared with the wild-type gene. This article reconsiders the important role of the NET protein in the regulation of the nervous and cardiovascular systems, reviews the literature for its polymorphisms and their suggested clinical manifestations, and finally focuses on the effects of its defect on the pathophysiology of OI, the only confirmed direct association between a genetic mutation of the NET and a clinical syndrome. Genetic or acquired deficits inthe norepinephrine transporter: current understanding of clinical implications 2 expert reviews in molecular medicine References 1 Young, J.B. and Landsberg, L. (1998) Catecholamines and the adrenal medulla. In Accession information: (01)00387-8a.pdf (short code: txt001drn); Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications 8 expert reviews in molecular medicine Accession information: (01)00387-8a.pdf (short code: txt001drn);

The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer's disease: A post-mortem autoradiographic study

“…Changes in NET density may be result of genetic polymorphism, neurological and psychiatric diseases, physiological ageing or the pharmacological effects of therapeutic or abused drugs (Klimek et al, 1997;Tellioglu and Robertson, 2001). Due to its early decrease in neurodegenerative diseases, including AD, NET appears to be a useful biomarker of disease.…”

REM sleep and its Loss-Associated Epigenetic Regulation with Reference to Noradrenaline in Particular

“…NAT is a monoamine transporter responsible for sodium–chloride dependent re-uptake of NA. This re-uptake is essential for maintenance of NA level at the synaptic cleft and its biological effects, including adrenergic neurotransmission in the brain, heart and peripheral organs [ 35 ]. Various adrenoreceptor isoforms e.g.…”

Role of GNB3, NET, KCNJ11, TCF7L2 and GRL genes single nucleotide polymorphism in the risk prediction of type 2 diabetes mellitus

“…This could possibly occur as a result of various mutations and polymorphisms where a single nucleotide changes in the gene neither encoding nor epinephrine transporter may result in a non functional protein. A lot of studies have been conducted globally to find a potential relationship between single nucleotide polymorphism in NET gene and various diseases such as psychiatric disorders (Tellioglu and Robertson 2001), hyperactivity disorder (Kim et al 2006), ADHD (Shannon et al 2000; Neubauer and Christensen 1976) orthostatic intolerance (Tellioglu and Robertson 2001; Shannon et al 2000) etc. Neubauer in 1976 first reported that norepinephrine concentration reduces considerably in the cardiovascular system of the diabetic patients but till date an insignificant amount of data is present to provide a potential evidence of the association of NET gene polymorphism with T2DM.…”