Serotonin Decreases Alveolar Epithelial Fluid Transport via a Direct Inhibition of the Epithelial Sodium Channel

Abstract

Hypoxia and epithelial stretch that are commonly observed in patients with acute lung injury have been shown to promote the release of serotonin (5-hydroxytryptamine, 5-HT) in vitro. However, whether 5-HT contributes to the decrease of alveolar epithelial fluid transport, which is a hallmark of lung injury, is unknown. Thus, we investigated the effect of 5-HT on ion and fluid transport across the alveolar epithelium. 5-HT caused a dose-dependent inhibition of the amiloride-sensitive current across primary rat and human alveolar epithelial type II cell monolayers, but did not affect Na 1 /K 1 ATPase function. Furthermore, we found that the 5-HT induced inhibition of ion transport across the lung epithelium was receptor independent, as it was not prevented by the blockade of 5-HT2R (5-HT receptor 2), 5-HT3R (5-HT receptor 3), or by pretreatment with an intracellular calcium-chelating agent, BAPTA-AM (1,2-bis(oaminophenoxy)ethane-N,N,N9,N9-tetraacetic acid tetra(acetoxymethyl) ester). In addition, the stimulation of 5-HT1R (5-HT receptor 1), 5-HT2R (5-HT receptor 2), 5-HT4R (5-HT receptor 4), and 5-HT7R (5-HT receptor 7) failed to reproduce the 5-HT effect on amiloridesensitive sodium transport. We ascertained that 5-HT directly inhibited the function of rat abg epithelial sodium channel (ENaC), as determined by heterologous expression of rat ENaC in Xenopus oocytes that do not express endogenous ENaC nor 5-HT receptors (5-HTR). Exposure of mice to hypoxia for 1 hour induced a 30% increase of 5-HT secretion into the distal airways of mice. Finally, the intratracheal instillation of 5-HT inhibited the amiloride-sensitive fraction of alveolar fluid clearance in mice. Together, these results indicate that 5-HT inhibits the amiloride-sensitive fraction of the alveolar epithelial fluid transport via a direct interaction with ENaC, and thus can be an endogenous inhibitor of this ion channel.

MicroRNA 16 modulates epithelial sodium channel in human alveolar epithelial cells

“…It was shown that serotonin decreases alveolar epithelial fluid transport via a direct inhibition of epithelial sodium channel [8] . Many studies suggest that defects in alveolar epithelial fluid transport can lead to pulmonary edema [5] .…”

“…Several studies have found that ENaC is the major determinant of alveolar fluid clearance across the alveolar epithelium. Earlier studies have demonstrated that serotonin (5-HT) significantly inhibits amiloride-sensitive sodium transport across rat and human lung alveolar epithelial cell monolayers via a receptor-independent inhibition of ENaC activity [8] . As 5-HT also significantly inhibits the amiloride-sensitive fraction of the alveolar fluid clearance in mice, 5-HT can be considered as an endogenous inhibitor of ENaC.…”

MicroRNA-7-5p regulates human alveolar epithelial sodium channels by targeting the mTORC2/SGK-1 signaling pathway

“…Increased ENaC subunit expression and elevated ENaC activity can significantly promote AFC. [20] mTORC2 is a PIKK family member, which is composed of mTOR, Rictor, mSIN1, PRR5, and mLST8. This compound is rapamycin insensitive and plays an important role in the regulation of sodium transport channels and the protein translation process.…”

Neuroendocrine Signaling Via the Serotonin Transporter Regulates Clearance of Apoptotic Cells

“…5-HT also has a variety of important endocrine-like functions outside of the CNS, which include its ability to regulate vasoconstriction, proliferation, osteoclastogenesis, insulin secretion, and platelet function (1)(2)(3)(4)(5)(6)(7). The literature also suggests that 5-HT is an important regulator of the immune system with a role in the pathogenesis of autoimmunity (8,9), inflammatory bowel disease (10 -12), pulmonary hypertension (13,14), acute lung injury (15,16), asthma (17), and chronic obstructive pulmonary disease (18 -21).…”