The norepinephrine transporter and its regulation

Abstract

For many years, the norepinephrine transporter (NET) was considered a 'static' protein that contributed to the termination of the action of norepinephrine in the synapse of noradrenergic neurons. The concept that the NET is dynamically regulated, adjusting noradrenergic transmission by changing its function and/or expression, was considered initially in the mid 1980s. Since that time, a plethora of studies demonstrate that the NET is regulated by several intracellular and extracellular signaling molecules, and that phosphorylation of the NET is a major pathway regulating its cell surface expression and thereby its function. The NET is a target of action of a number of drugs that are used long-term therapeutically or abused chronically. This has driven numerous investigations of how the NET and its function are regulated by long-term exposure to drugs. While repeated exposure to many drugs has been shown to affect NET function and expression, the intracellular mechanisms for these effects remains elusive.

Effects of the Noradrenergic System in Rat White Matter Exposed to Oxygen–Glucose DeprivationIn Vitro

“…The uptake of NE into cells is performed by NET, a member of a large family of transporters that concentrate NE by cotransport with Na ϩ and Cl Ϫ (Mandela and Ordway, 2006). During metabolic inhibition, a decrease of ATP levels followed by inhibition of Na ϩ /K ϩ ATPase activity leads to intracellular Na ϩ accumulation and reversal of the NET, resulting in release of transmitter (Vizi, 2000).…”

Appropriate dosing regimens for treating juvenile rats with desipramine for neuropharmacological and behavioral studies

“…It is known to inhibit the norepinephrine transporter (NET) and down-regulate beta adrenergic receptors (Bauer and Tejani-Butt, 1992;Hebert et al, 2001;Mandela and Ordway, 2006;Argenti and D'Mello, 1994b;Hebert et al, 2001). In rats (although not in humans) the major metabolite of DMI, desmethyldesipramine (DDMI), is active and has been shown to down-regulate beta adrenergic receptors (Argenti and D'Mello, 1994b).…”

Pentazocine Inhibits Norepinephrine Transporter Function by Reducing its Surface Expression in Bovine Adrenal Medullary Cells

“…One common pathway is phosphorylation by several protein kinases such as cAMP-dependent protein kinase and protein kinase C (15,28). Activation of protein kinase C is reported to down-regulate the function of NET in SK-N-SH cells (29) or transfected COS-7 cells (30).…”