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. 2016 Dec 19;10:564. doi: 10.3389/fnins.2016.00564

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Copyright © 2016 Linan-Rico, Ochoa-Cortes, Beyder, Soghomonyan, Zuleta-Alarcon, Coppola and Christofi.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Working Hypothesis of mechanotransduction in EC cells. Mechanical stress (MS) activates a mechanosensor in EC and epithelial cells to induce release of 5′nucleotide triphosphates (NTP) such as ATP and UTP that act in an autocrine or paracrine manner to modulate 5-HT release. The Piezo 2 mechanogated channel was recently identified as a critical component of the mechanosensor and mechanotransduction signaling pathway activated by MS in EC cells leading to 5-HT release (in pathways 1 and 2 in the diagram). Mechanically evoked NTP release activates a predominant P2Y₁/G_αq/PLC/PIP₂/IP₃/IP₃R/SERCA pump–Ca²⁺signaling pathway leading to 5-HT release. Caveolin-1 (CAV-1) associated with cholesterol-rich micro-domains in caveolae (specialized invaginations in the lipid bilayer of the EC cell membrane) forms a scaffold to support the functional coupling of the P2Y₁-GPCR, Gαq, PLC and NTP secretion from the cell. In this model, caveolae and cholesterol rich caveolin-1 microdomains are essential for both NTP release and down-stream Ca²⁺dependent 5-HT release. Therefore, manipulations that disrupt the structure or assembly of caveolae by treating cells to filipin or β-cyclodextrin (β-CD) prevent the mechanically evoked NTP (ATP) and 5-HT secretion. A minor mechanosensitive pathway is an A₂/Gs/AC-cAMP/PKA signaling pathway of 5-HT release. Ca²⁺ and cAMP-dependent transcriptional regulation occurs in response to mechanical stimulation that can further modulate EC cell function(s). In this model, it is postulated that Piezo 2 activation could also stimulate 5-HT secretion via a separate purine-independent pathway (pathway 2 in diagram).