cathepsin g br Role of OCT in histamine

Role of OCT3 in histamine clearance Histamine is a powerful neuromodulator, as well as a regulator of immune processes and vascular tone in the central nervous system (Gross, 1981; Haas et al., 2008; Jutel et al., 2006). In contrast to 5-HT and the catecholamines, a high-affinity transporter for histamine has not been identified. Thus, OCT3 and other uptake2 transporters may constitute the major histamine transporters in the central nervous system and in peripheral tissues. Indeed, previous studies have demonstrated that OCT3 mediates histamine uptake by peripheral immune cells (Nakamura et al., 2017; Schneider et al., 2005). In the central nervous system, recent studies have indicated roles for OCT3 and PMAT in the uptake of histamine by cultured astrocytes (Yoshikawa et al., 2013). The specific roles of various uptake2 transporters in the clearance of extracellular histamine, and the effects of corticosterone on histaminergic neurotransmission represent important areas for future study.
Implications and future directions Since the description of a corticosteroid-sensitive catecholamine clearance system (uptake2) in cardiovascular tissue in the 1960s, and the identification of the multi-specific, corticosterone-sensitive monoamine transporter OCT3 as a major mediator of uptake2, it has become clear that this transport system also contributes significantly to monoamine transport in the central nervous system. Despite these advances, the contribution of OCT3, relative to sodium-dependent, high affinity, low capacity monoamine transporters, or other transporters, to monoamine clearance under baseline or stress conditions is not known and developing a clear answer to this question will require development of new methodological approaches and further study. The demonstration that OCT3 and other uptake2-like transporters are expressed in the cathepsin g has profound implications for our understanding of the mechanisms that regulate monoaminergic neurotransmission. In areas where OCT3 is expressed, the clearance of monoamines will be, at least in part, inhibited under conditions of elevated corticosteroid hormones, including during times of acute and chronic stress. The studies described here have revealed a small number of pathways in which corticosteroid-induced inhibition of OCT3-mediated monoamine transport regulates monoamine clearance and behavior, acting through rapid, nongenomic mechanisms. Because of its widespread distribution in the brain, and its expression in multiple cell types and subcellular locations, it is very likely that more pathways and behaviors regulated in part by OCT3 will be described in the future. Key outstanding questions remain. The precise roles of OCT3 in mediating monoamine clearance are not fully described. This will require ultrastructural studies that examine the relative localizations of OCT3 and the uptake1 transporters NET, DAT, and SERT. In addition, a greater understanding of the effects of OCT-mediated monoamine transport, and its inhibition by corticosteroids, on activation of the receptors for monoamines requires knowledge of the proximity of OCT3 to these receptors. Due to its low affinity and high capacity, OCT3 has the potential to limit the physical spread of monoamines to nearby receptors and, when inhibited by steroids, to enhance their activation. Future studies must test these hypotheses. In the absence of specific inhibitors of OCT3, the contribution of the transporter to stress- and glucocorticoid-induced physiological and behavioral responses must be explored using targeted genetic approaches, and the search for specific inhibitors must continue. Despite the gaps in our knowledge, it is clear that OCT3 represents a cellular mechanism by which stress, through elevation of glucocorticoid hormones and rapid, nongenomic actions, may exert powerful modulatory influence over the actions of norepinephrine, DA, 5-HT and histamine and thus over physiological and behavioral responses to these monoamines.