Transient receptor potential (TRP) channels function as cellular sensors to perceive and respond to a variety of environmental stimuli including temperature, pain, pressure and fluid flow.These channels can be divided into seven subfamilies, including TRPV, TRPC, TRPP, and four others.Functional TRP charmels are tetrameric complexes consisting of four pore-forming subunits, which could be identical (homotetrameric channels) or different (heterotetrameric channels).In the present study, we found that TRPV4,-C1, and-P2 associate together to form a physical complex.In function study, this TRPV4-C1-P2 complex mediates flow-induced Ca2+ influx in HEK293 cells over-expressing TRPV4,-C1, and-P2 and in rat mesenteric artery endothelial cells (MAECs).Pore-dead mutant of each of these three TRP isoforms abolished or markedly reduced the flow-induced cation currents and Ca2+ rises, suggesting all three TRPs contribute to the ion permeation pore of the channels.Taken together, we identified the first heteromeric TRP channels composed of subunits from three different TRP subfamilies, namely heteromeric TRPV4-C1-P2 channels.Functionally, heteromeric TRPV4-C1-P2 are the main channels that mediate flow-induced Ca2+ rises in native vascular endothelial cells, thus plays a key role in the control of vascular tone and blood pressure.