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 V_max. 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⁺.