Abstract
We investigated phosphorylation-mediated regulation of functions of monoamine transporters, which are known as main molecular targets of antidepressants. Noradrenaline (NA) uptake in PC12 cells was enhanced by activation of calmodulin-dependent protein kinases such as Ca2+/calmodulin-dependent kinase II (CaM kinase II) and myosin light chain kinase, probably through stimulation of translocation of NA transporter (NAT) to plasma membrane and/or direct phosphorylation of the transporter itself. Also long-term activation of CaM kinase II increased NA uptake by stimulating NAT gene expression probably through phosphorylation of transcription factors such as CREB. These findings indicate that functions of monoamine transporters may be regulated both acutely and chronically by calmodulin-dependent protein kinases. Furthermore, long-term addition of antidepressants (desipramine and nisoxetine) which selectively inhibit NA uptake decreased NAT mRNA in PC12 cells, suggesting that chronic treatment of antidepressants affects expression of monoamine transporters. Recently, partial association between polymorphism of serotonin transporter gene and neuroticism or affective disorder has been reported. Therefore, reanalysis of monoamine transporter-related neuronal functions might be needed to elucidate neurochemical pathogenesis of depression and therapeutic mechanism of antidepressants.
