Identification of a novel regulatory mechanism for norepinephrine transporter activity by the IP3 receptor.
The norepinephrine transporter (NET) plays a crucial role in noradrenergic neurotransmission and is a target of many antidepressants and psychostimulants. Intracellular Ca2+ is reportedly involved in regulating NET activity, but the detailed mechanism is not clear. We employed a norepinephrine uptake assay using SH-SY5Y cells and found that the IP3 receptor inhibitors, 2-aminoethoxydiphenyl borate and xestospongin C, reduced the NET Vmax. These reductions were accompanied by the decreased cell surface expression of NET. Our findings suggest that intracellular Ca2+ mobilized by IP3 receptor is required for the maintenance of NET activity. This adds another pathway involving Ca2+ for the regulation of NET to other known mechanisms providing intracellular Ca2+.
Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Taiju
T
Amano
Shunsuke
S
Aoki
Rieko
R
Setsuie
Mikako
M
Sakurai
Keiji
K
Wada
Mami
M
Noda
D001692:Biological Transport / Q000187:drug effects; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D047028:Macrocyclic Compounds; D009638:Norepinephrine / Q000493:pharmacokinetics; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000502:physiology*
D001896:Boron Compounds; D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; C108644:xestospongin A; D002217:Carbachol; C109986:2-aminoethoxydiphenyl borate; D002118:Calcium; D009638:Norepinephrine