Endothelin-1 and -3 modulate the neuronal norepinephrine transporter through multiple signalling pathways in the rat posterior hypothalamus

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

“…At present, no reports have linked presynaptic receptor activation to CaMKII-dependent changes in NET function, trafficking, or protein associations. By using inhibitors, Hope and colleagues found no contributions of CaMKII pathways to endothelin regulation of NET activity in rat hypothalamic preparations, although KN-62 had basal inhibitory effects (Hope et al, 2010). Lu et al (1996) found rapid, stimulatory actions of angiotensin II on hypothalamic NET activity mediated by AT1 receptors, effects consistent with elevations in NET surface expression found by Savchenko et al (2003) after angiotensin II treatments.…”

“…Several studies indicate that NET-mediated NE transport activity is positively regulated by CaMKII-linked pathways. Thus, Apparsundaram et al (1998a) found that treatment of noradrenergic SK-N-H cells with KN-93 induced a rapid reduction in NET activity, effects reproduced in other models (Mandela and Ordway, 2006;Sung and Blakely, 2007;Hope et al, 2010). Conversely, Uchida et al (1998), studying rat PC-12 cells found that elevation of extracellular Ca 2+ enhanced NET activity, relative to Ca 2+ free medium, in a calmodulin and CaMKII inhibitor-sensitive manner, effects mediated by an increase in NE uptake V max and a reduction in NE K M .…”

“…A role for PKC may also be involved in the regulation of NE uptake by the endothelins ET-1 and ET-3, with evidence arising through studies of rat hypothalamic ET B receptors (Hope et al, 2010). These investigators found that activation of ET B receptors by these peptides decreased NE uptake effects blocked by the PKC in- (Hope et al, 2008).…”

“…However, Callado and Stamford (2000) were unable to detect an influence on endogenous NE clearance assessed by fast cyclic voltammetry of the a2 antagonist BRL 4408 (2-[2H-(1-methyl-1,3-dihydroisoindole) methyl]-4,5-dihydroimidazole) was applied to locus ceruleus brain slices. With respect to heteroreceptors, Hope and colleagues obtained evidence for cAMP-dependent modulation of NE uptake in hypothalamic preparations downstream of endothelin 1 and 3 receptors (Hope et al, 2008(Hope et al, , 2010Vatta et al, 2015), effects likely mediated by changes in NET trafficking. These receptors however do not couple directly to cAMP production, and thus the cAMP dependence of effects are likely indirect.…”

The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity

“…An important concept now emerging is that receptormediated signaling events in monoaminergic neurons are the principal drivers of the phosphorylation-dependent mechanisms that in turn affect monoamine transporter functional regulation (e.g. Gulley and Zahniser 2003;Middleton et al 2004;Chefer et al 2005;Zapata et al 2007;Zhu et al 2007;Xie and Miller 2009a;Reyes et al 2009;Iceta et al 2009;Hope et al 2010;Bowton et al 2010). Accordingly, the ability of monoamine transporters to enhance TAAR1 signaling raised the possibility that the enhanced signaling of TAAR1 could in turn alter functional aspects of monoamine transporters.…”