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Amino acid sequence alignment of the ion channel domain of representative members of the TRP superfamily of cation channels: TRPC3, TRPM2, TRPP2, TRPA1, TRPML1, and TRPV1. Amino acids shown in white on a black background denote three identities among the six sequences. The consensus sequence is shown in bold. Note that there is significant sequence similarity among members of the TRP channel superfamily.

Signaling and regulation of TRPP2 channels. This illustration depicts the different models for the localization-dependent functions of TRPP2. TRPP2 mediates Ca²⁺ influx at the plasma membrane (PM) and the ciliary membrane (cilium), where it functions in a heteromultimeric protein complex with PKD1 (1, 3) and possibly with other members of the TRP channel superfamily (TRPC1, TRPV4) (2). PKD1 is known to activate multiple signaling pathways via G proteins, a process that can be regulated by physical interaction with TRPP2. Calcium influx induced by shear flow in renal epithelial cells is triggered by bending the primary cilium and seemingly requires the PKD1–TRPP2 complex in the luminal cilium (3). Mechanical stress activates PKD1–TRPP2 complexes to allow Ca²⁺ influx either in the shaft or in the base of the primary cilium. TRPP2 acts as a Ca²⁺-release channel in the endoplasmic reticulum (ER), where it might interact with and regulate IP₃Rs (4). Serine-phosphorylated TRPP2 sequesters Id2 in the cytoplasm and normally prevents Id2 from entering the nucleus and binding to E-proteins (5). PKD1 can undergo a proteolytic cleavage that releases its C-terminal tail, which translocates to the nucleus and activates the transcription factor AP-1 (6). Note that we hypothetized that PKD1 targeted to the primary cilium is also cleaved at its GPS site. See text for more details. Abbreviations: PKC, protein kinase C; PKA, cAMP-dependent protein kinase; NFAT, nuclear factor of activated T-cells; PI3K, phosphatidylinositol 3-kinase; MEK, mitogen-activated protein kinase/ERK kinase; ERK, extracellular signal-regulated kinase.