Gating Mechanisms of Canonical Transient Receptor Potential Channel Proteins: Role of Phosphoinositols and Diacylglycerol
Anthony P. Albert
Canonical transient receptor potential (TRPC) Ca2+-permeable channels are members of the mammalian TRP super-family of cation channels, and have the closest homology to the founding members, TRP and TRPL, discovered in Drosophila photoreceptors. The TRPC subfamily is composed of 7 subunits (C1–C7, with TRPC2 a pseudogene in humans), which can all combine with one another to form homomeric and heteromeric structures. This review focuses on mechanisms involved in opening TRPC channels (i.e. gating mechanisms). It initially describes work on the involvement of phosphatidylinositol-4,5-bisphosphate (PIP2) and diacylglycerol (DAG) in gating TRP and TRPL channels in Drosophila, and then discusses evidence that similar gating mechanisms are involved in opening mammalian TRPC channels. It concludes that there are two common activation pathways of mammalian TRPC channels. Non-TRPC1-containing channels are opened by interactions between DAG, the direct activating ligand, and PIP2, which acts as a physiological antagonist at TRPC proteins. Competitive interactions between an excitatory effect of DAG and an inhibitory action of PIP2 can also be modulated by IP3 acting via an IP3 receptor-independent mechanism. In contrast TRPC1-containing channels are gating by PIP2, which requires PKC-dependent phosphorylation of TRPC1 proteins.