Figure 1.

Proposed scheme, illustrating the involvement of TRPV4 in mechanosensitivity in the distal nephron cells. PLA₂ – phospholipase A₂, AA – arachidonic acid, CYP450 – cytochrome P450 epoxygenase, EETs – epoxyeicosatrienoic acids, – proline rich domain, PC-1 – polycystin-1, PKC – protein kinase C, PLC- phospholipase C, P2Y2R – P2Y2 receptor, Cx30 – connexin 30 hemichannel. In the kidney TRPV4 forms a heteromeric channel with polycystin-2 (TRPP2), which is a part of a larger mechanosensitive complex also involving of PC-1. Mechanical stress stimulates PLA₂ – CYP450 pathway, which metabolizes AA to EETs. EETs activate TRPV4 channel to elicit Ca²⁺ influx in response to hypotonicity or elevated flow. This activation can be prevented by interaction of TRPV4 N-terminal proline rich domain with PACSIN 3 protein. On the other hand, mechanical stimuli induce ATP release from distal nephron cells through Cx30 hemichannels. Locally released ATP binds to purinergic P2Y2 receptors on the apical membrane of renal epithelium. This leads to G_q/11 dependent activation of PLC and, likely, PKC and further augmenting TRPV4 activity.