Organic Cation Transporter 3 (Slc22a3) Is Implicated in Salt-Intake Regulation

Abstract

Organic cation transporters (OCTs) are carrier-type permeases known to participate in general detoxification functions in peripheral tissues. Previous in vitro studies have suggested that OCTs ensure Uptake 2 , a low-affinity, corticosteroid-sensitive catecholamine removal system, which was characterized initially in sympathetically innervated tissues. Although the presence of both Uptake 2 -like transport and most OCT subtypes has also been demonstrated in the brain, the physiological role of this family of transporters in CNS remained totally unknown. In the present work, we show that the OCT3 transporter is found throughout the brain and highly expressed in regions regulating fluid exchange, including circumventricular organs such as area postrema and subfornical organ (SFO), and in other structures implicated in the sensing of changes in blood osmolarity and regulation of salt and water ingestion. OCT3/Slc22a3-deficient mice show an increase in the level of ingestion of hypertonic saline under thirst and salt appetite conditions, as well as alterations of the neural response in the SFO after sodium deprivation, as monitored by Fos immunoreactivity. This work demonstrates that the presence of OCT3 is critical for the balanced neural and behavioral responses to environmentally induced variations in osmolarity and provides for the first time physiological evidence of the importance of OCTs for CNS function.

Transport of Biogenic Amine Neurotransmitters at the Mouse Blood–Retina and Blood–Brain Barriers by Uptake1 and Uptake2

“…However, these uptake1 transporters were not detected in the endothelium, either luminally or abluminally. The anti-Oct3 antibody labeled some fibers in the mouse brain, particularly near the ventricles ( Figure 5B), in agreement with previous reports (Amphoux et al, 2006;Vialou et al, 2004). However, we detected no Oct3 in the cerebral vessels, suggesting that this transporter is not present at the BBB.…”

“…The isolation and culture of endothelial cells for use in in vitro BBB models often leads to the dysregulation of transporters (Lyck et al, 2009). Moreover, brain extracellular fluid microdialysis sampling experiments do not discriminate between the kinetic processes at the BBB and those at the other brain extracellular fluid/ intracellular fluid interfaces where these transporters are present (e.g., neurons and ventricles) (Amphoux et al, 2006;Vialou et al, 2004). Our results indicate that the luminal BBB permeability to MPP + , a broad, high-capacity substrate of biogenic amine uptake1 and uptake2 transporters, and the organic cation transporter Mate1, is not carrier mediated.…”

“…The following primary antibodies were used: a mouse monoclonal anti-P-gp (C219, Alexis Biochemicals, San Diego, CA, USA, diluted 1:50), a rat monoclonal anti-Bcrp (BXP53, Alexis Biochemicals, diluted 1:50), a mouse monoclonal anti-Net (NET05-1, MabTechnologies, Stone Mountain, GA, USA, diluted 1:600) raised against the N-terminal intracellular domain (residues 5 to 17) and previously characterized (Matthies et al, 2009), a rat polyclonal anti-Dat (Chemicon MAB369; Millipore, Molsheim, France, diluted 1:1,000), a rabbit antiserum against Sert (Immunostar 24330; Euromedex, Souffelweyersheim, France, diluted 1:200), a rabbit antiserum against tyrosine hydroxylase (208020234, Jacques Boy, Reims, France, diluted 1:4,000), a mouse monoclonal anti-Pmat (ab56554, Abcam, Cambridge, UK, diluted 1:100), and a rabbit polyclonal anti-Oct3 (OCT31-S, Alpha Diagnostic, San Antonio, TX, USA) previously characterized (Vialou et al, 2004). Appropriate goat secondary antibodies conjugated to Alexa Fluor-488 or 555 dyes (Life Technologies, Saint Aubin, France, diluted 1:300) were used for detection.…”

Adrenaline and Noradrenaline: Partners and Actors in the Same Play"

“…Consistently, high expression has been reported for placenta and heart (Eisenhofer, 2001). Other reports indicate high extraneuronal monoamine transporter expression in the area postrema (Haag et al, 2004, Vialou et al, 2004 and very low in the kidneys (Eisenhofer, 2001). Interestingly, extraneuronal monoamine transporter expression has been also suggested to occur in neurons (Kristufek et al, 2002, Shang et al, 2003.…”

SLC22A3 (Solute carrier family 22 member 3)

“…SLC22A3 is expressed in a wide range of tissues including the first-trimester and term placenta, skeletal muscle, prostate, liver, aorta, fetal lung, salivary gland, adrenal gland (Verhaagh et al, 1999), sympathetically innervated tissues (Lazar et al, 2003), heart, brain (Vialou et al, 2004;Chen et al, 2010), central nervous system (Zhu et al, 2012) and kidney (Wu et al, 2000).…”