Chronic and acute regulation of Na+/Cl–-dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems

Zahniser, Nancy R.; Doolen, Suzanne

doi:10.1016/s0163-7258(01)00158-9

Cited by 256 publications

(226 citation statements)

References 277 publications

Supporting

Mentioning

218

Contrasting

Unclassified

Order By: Relevance

“…Although it is well established that PKC activation acutely downregulates DAT (Zahniser and Doolen, 2001;Robinson, 2002;Torres et al, 2003a;Melikian, 2004), the specific mechanisms mediating PKC-induced losses in DAT function are not well defined. Numerous studies from both our laboratory (Melikian and Buckley, 1999;Loder and Melikian, 2003;Holton et al, 2005) and others (Zhu et al, 1997;Granas et al, 2003;Sorkina et al, 2005) have demonstrated a clear role for endocytic trafficking in maintaining basal DAT surface levels and mediating PKC-induced DAT downregulation.…”

Section: Discussionmentioning

confidence: 99%

Dopamine transporter endocytic determinants: Carboxy terminal residues critical for basal and PKC-stimulated internalization

Boudanova

Navaroli

Stevens

et al. 2008

Molecular and Cellular Neuroscience

View full text Add to dashboard Cite

Dopamine (DA) reuptake terminates dopaminergic neurotransmission and is mediated by DA transporters (DATs). Acute protein kinase C (PKC) activation accelerates DAT internalization rates, thereby reducing DAT surface expression. Basal DAT endocytosis and PKC-stimulated DAT functional downregulation rely on residues within the 587-596 region, although whether PKCinduced DAT downregulation reflects transporter endocytosis mechanisms linked to those controlling basal endocytosis rates is unknown. Here, we define residues governing basal and PKCstimulated DAT endocytosis. Alanine substituting DAT residues 587-590 1) abolished PKC stimulation of DAT endocytosis, and 2) markedly accelerated basal DAT internalization, comparable to that of wildtype DAT during PKC activation. Accelerated basal DAT internalization relied specifically on residues 588-590, which are highly conserved among SLC6 neurotransmitter transporters. Our results support a model whereby residues within the 587-590 stretch may serve as a locus for a PKC-sensitive braking mechanism that tempers basal DAT internalization rates.

show abstract

Section: Discussionmentioning

confidence: 99%

Dopamine transporter endocytic determinants: Carboxy terminal residues critical for basal and PKC-stimulated internalization

Boudanova

Navaroli

Stevens

et al. 2008

Molecular and Cellular Neuroscience

View full text Add to dashboard Cite

show abstract

“…The Na ϩ -and Cl Ϫ -dependent neurotransmitter transporters are believed to be tightly regulated, making the protein kinase C (PKC)-mediated regulation the most studied mechanism (34,35). Activation of PKC by phorbol esters such as 4␣-phorbol 12-myristate 13-acetate (PMA), leads to acute reduction in transport activity of the monoamine transporters, the ␥-aminobutyric acid transporter GAT-1 and GLYT1 (35).…”

mentioning

confidence: 99%

The Second Intracellular Loop of the Glycine Transporter 2 Contains Crucial Residues for Glycine Transport and Phorbol Ester-induced Regulation

Fornés

Núñez

Aragón

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Na ؉ and Cl ؊ -coupled glycine transporters control the availability of glycine neurotransmitter in the synaptic cleft of inhibitory glycinergic pathways. In this report, we have investigated the involvement of the second intracellular loop of the neuronal glycine transporter 2 (GLYT2) on the protein conformational equilibrium and the regulation by 4␣-phorbol 12 myristate 13-acetate (PMA). By substituting several charged (Lys-415, Lys-418, and Lys-422) and polar (Thr-419 and Ser-420) residues for different amino acids and monitoring plasma membrane expression and kinetic behavior, we found that residue Lys-422 is crucial for glycine transport. The introduction of a negative charge in 422, and to a lower extent in neighboring N-terminal residues, dramatically increases transporter voltage dependence as assessed by response to high potassium depolarizing conditions. In addition, [2-(trimethylammonium)ethyl] methanethiosulfonate accessibility revealed a conformational connection between Lys-422 and the glycine binding/permeation site. Finally, we show that the mutation of positions Thr-419, Ser-420, and mainly Lys-422 to acidic residues abolishes the PMA-induced inhibition of transport activity and the plasma membrane transporter internalization. Our results establish a new structural basis for the action of PMA on GLYT2 and suggest a complex nature of the PMA action on this glycine transporter.

show abstract

“…[8][9][10] hNET is a transmembrane protein (617 amino acids), which belongs to a family of Na þ /Cl --dependent transporters and mediates the re-uptake transport of norepinephrine, dopamine and epinephrine from the presynaptic membrane. 11,12 Human, bovine, rat and mouse norepinephrine transporter complementary DNAs (cDNAs) have been cloned. 11,13 However, hNET is only expressed in a narrow range of tumor types.…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo studies of adenovirus-mediated human norepinephrine transporter gene transduction to hepatocellular carcinoma

Huang

et al. 2010

Cancer Gene Ther

View full text Add to dashboard Cite

The clinical value of 131 I-MIBG for targeted imaging and targeted radiotherapy is limited to neural crest-derived tumors expressing human norepinephrine transporters (hNET) protein. To extend 131 I-MIBG-targeted therapy to other nonexpressed hNET tumors, this study investigated the hNET expression in vitro and in vivo in HepG2 hepatoma mediated by recombinant adenovirus encoding the hNET gene (Ad-hNET). For this purpose, the HepG2 cells showed a 4.87-fold increase in 125 I-MIBG uptake after infection with Ad-hNET, and the uptake of 125 I-MIBG could be specifically inhibited by maprotiline. Immunohistological analysis, in vivo biological study and 131 I-MIBG scintigraphic imaging also revealed the high expression of hNET protein in hepatoma. This in vitro and in vivo studies demonstrate the feasibility of hNET gene transfer, meditated by adenovirus vector, could extend to tumors other than those derived from the neural crest, which provides a sound foundation for further investigation of hepatocellular carcinomatargeted radiotherapy mediated by adenovirus transfection with hNET gene.

show abstract

Chronic and acute regulation of Na+/Cl–-dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems

Cited by 256 publications

References 277 publications

Dopamine transporter endocytic determinants: Carboxy terminal residues critical for basal and PKC-stimulated internalization

Dopamine transporter endocytic determinants: Carboxy terminal residues critical for basal and PKC-stimulated internalization

The Second Intracellular Loop of the Glycine Transporter 2 Contains Crucial Residues for Glycine Transport and Phorbol Ester-induced Regulation

In vitro and in vivo studies of adenovirus-mediated human norepinephrine transporter gene transduction to hepatocellular carcinoma

Contact Info

Product

Resources

About