Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior

Abstract

Transporter-mediated uptake determines the peak concentration, duration, and physical spread of released monoamines. Most studies of monoamine clearance focus on the presynaptic uptake transporters SERT, NET and DAT. However, recent studies have demonstrated the expression of the uptake transporter OCT3 (organic cation transporter 3), throughout the rodent brain. In contrast to NET, DAT and SERT, OCT3 has higher capacity and lower affinity for substrates, is sodium-independent, and is multi-specific, with the capacity to transport norepinephrine, dopamine, serotonin and histamine. OCT3 is insensitive to inhibition by cocaine and antidepressant drugs but is inhibited directly by the glucocorticoid hormone corticosterone. Thus, OCT3 represents a novel, stress hormone-sensitive, monoamine transport mechanism. Incorporating this transporter into current models of monoaminergic neurotransmission requires information on: A) the cellular and subcellular localization of the transporter; B) the effects of OCT3 inhibitors on monoamine clearance; and C) the consequences of decreased OCT3-mediated transport on physiology and/or behavior. This review summarizes studies describing the anatomical distribution of OCT3, its cellular and subcellular localization, its contribution to the regulation of dopaminergic signaling, and its roles in the regulation of behavior. Together, these and other studies suggest that both Uptake and Uptake transporters play key roles in regulating monoaminergic neurotransmission and the effects of monoamines on behavior.

Dopamine Evokes a Trace Amine Receptor-dependent Inward Current that is Regulated by AMP Kinase in Substantia Nigra Dopamine Neurons

“…Although Mayer et al (2018) reported that midbrain dopamine neurons express OCT3 mRNA in mice, an immunohistological study by Cui et al (2009) found that OCT3 was expressed by astrocytes and non-dopamine neurons in the SNC but not by dopamine neurons. Although it is uncertain if dopamine neurons express OCT3, OCT3 has been shown to be insensitive to cocaine (Gasser, 2019;Mayer et al, 2018), which would agree with our finding that dopamine (in the presence of an AMPK inhibitor) can evoke an inward current despite the presence of a DAT inhibitor. If dopamine can be transported by OCT3 into dopamine neurons, our results would suggest that this transporter is tonically inhibited by AMPK.…”

Organic cation transporter 3 and the dopamine transporter differentially regulate catecholamine uptake in the basolateral amygdala and nucleus accumbens

“…Studies examining the relative subcellular localizations of DAT and OCT3 and their proximity to dopamine receptors would be particularly informative. While colocalization of these transporters has not been examined (Gasser, 2018), ultrastructural studies have demonstrated that OCT3 is localized to dendritic spines and presynaptic terminals in the BLA (Gasser et al., 2017), suggesting important roles for the transporter in regulating perisynaptic monoamine concentrations. OCT3 expression has also been observed on DAT+ neurons (Mayer et al., 2018), suggesting possible co‐expression at dopamine terminals.…”

“…These transporters also function to clear monoamines from the extracellular fluid and are inhibited to CORT. Among the Uptake 2 transporters, OCT3 has the highest sensitivity to CORT (Gasser, 2018) and is expressed at greater density in the NAcc and BLA than other OCT isoforms (Amphoux et al., 2006). PMAT is expressed in relatively similar levels between the NAcc and BLA (Dahlin, Xia, Kong, Hevner, & Wang, 2007) and has greater affinity for dopamine than norepinephrine (Duan & Wang, 2010).…”

“…Dopamine transporters (DAT), are high‐affinity, low‐capacity transport proteins abundantly expressed in the NAcc (Karkhanis et al., (2015); Gainetdinov et al., 1998; Gainetdinov et al., 1999; Budygin et al., 2002), but are less abundant in the BLA. A growing body of literature suggests that the organic cation transporter 3 (OCT3) (Baganz et al., 2010; Duan & Wang, 2010; Gasser, 2018; Gasser, Hurley, Chan, & Pickel, 2017; Gasser et al., 2006; Graf et al., 2013; Hill & Gasser, 2013; Iversen & Salt, 1970; Lightman & Iversen, 1969; Wieland, Hayer‐Zillgen, Bonisch, & Bruss, 2000), which is expressed in both the NAcc (Graf et al., 2013) and BLA (Hill & Gasser, 2013), can mediate uptake of a variety of monoamine species including serotonin (Baganz et al., 2010; Schmitt et al., 2003), norepinephrine (Duan & Wang, 2010), and dopamine (Gasser et al., 2006; Hill & Gasser, 2013). Compared to the DAT, OCT3 has a lower affinity for dopamine (Duan & Wang, 2010), but a higher capacity for dopamine transport (Zhu, Appel, Grundemann, & Markowitz, 2010).…”

Identification of the Tetraspanin CD9 as an Interaction Partner of Organic Cation Transporters 1 and 2

“…OCTs are polyspecific, electrogenic, pH-and Na + -independent, but voltage-dependent bidirectional transporters for OCs with species-and tissue-specific expression. 1 Indeed, OCTs are considered to be an important regulator of monoamine neurotransmitter concentration in the CNS, [2][3][4][5] and, because of their high expression in secretory organs such as the liver (OCT1) and the kidneys (OCT2), they play an important role in OC excretion. This fact is of particular importance considering their interaction with drugs such as the antidiabetic metformin and the anticholinergic drug trospium, whose excretion is mediated by OCT1 and OCT2.…”