Abstract
The norepinephrine (NE) transporter (NET) terminates noradrenergic signaling by clearing released NE at synapses. The activity of NET can be rapidly regulated by depolarization and receptor activation via Ca 2+ and kinase/phosphatase-linked pathways. The SNARE protein syntaxin 1A (SYN1A) interacts with NET and influences transporter surface trafficking and catalytic activity. In this study, we establish a link between changes in intracellular Ca 2+ and SYN1A/NET interactions. SYN1A influenced NE transport only in the presence of Ca 2+ in brain cortical synaptosomes. Although NET/SYN1A associations were sensitive to manipulations of Ca 2+ in CHO cells, in vitro binding experiments using purified NET and SYN1A fusion proteins demonstrated a lack of direct Ca 2+ sensitivity. Disruption of NET/SYN1A interaction abolished inhibition of NE transport by phorbol ester (PMA) to activate protein kinase C (PKC), but had no effect on transport inhibition by the Ca 2+ calmodulin kinase (CaMK) inhibitor KN93. Furthermore, PMA enhanced Ca 2+-dependent modulation of NE transport in synaptosomes. Our data reveal roles for SYN1A in the Ca 2+-dependent regulation of NET, likely reliant on regulation by PKC signaling, but independent of CaMK.
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