Integration of transient receptor potential canonical channels with lipids

Abstract

Transient receptor potential canonical (TRPC) channels are the canonical (C) subset of the TRP proteins, which are widely expressed in mammalian cells. They are thought to be primarily involved in determining calcium and sodium entry and have wide-ranging functions that include regulation of cell proliferation, motility and contraction. The channels are modulated by a multiplicity of factors, putatively existing as integrators in the plasma membrane. This review considers the sensitivities of TRPC channels to lipids that include diacylglycerols, phosphatidylinositol bisphosphate, lysophospholipids, oxidized phospholipids, arachidonic acid and its metabolites, sphingosine-1-phosphate, cholesterol and some steroidal derivatives and other lipid factors such as gangliosides. Promiscuous and selective lipid sensing have been detected. There appear to be close working relationships with lipids of the phospholipase C and A(2) enzyme systems, which may enable integration with receptor signalling and membrane stretch. There are differences in the properties of each TRPC channel that are further complicated by TRPC heteromultimerization. The lipids modulate activity of the channels or insertion in the plasma membrane. Lipid microenvironments and intermediate sensing proteins have been described that include caveolae, G protein signalling, SEC14-like and spectrin-type domains 1 (SESTD1) and podocin. The data suggest that lipid sensing is an important aspect of TRPC channel biology enabling integration with other signalling systems.

Figure 1

Abridged schematics for regulation of transient receptor potential canonical 5 (TRPC5) (left) and TRPC6 (right) channels by lipids in simplified mammalian cells. See the main text for details. Examples of regulation by other factors are included, but are not exhaustive. Abbreviations not provided in the main text are: Gd³⁺, gadolinium; Pb²⁺, lead; rTRX, reduced thioredoxin; OxPLR, putative oxidized phospholipid receptor (identity unknown); H₂O₂, hydrogen peroxide; chol., cholesterol; podo., podocin; AA, arachidonic acid. G_i/o and G_q/11 are different types of GTP-binding proteins. The integral phospholipase C (PLC) and phospholipase A₂ (PLA₂) enzymes are not shown. TRPC6 may also be stimulated through receptor tyrosine kinase (Hamdollah Zadeh et al. 2008, Ge et al. 2009). Tian et al. (2010) should be consulted for the proposed distinction of TRPC5 coupling to cell movement and TRPC6 to contraction. Vesicular trafficking of TRPC5 has been described in response to growth factors (Bezzerides et al. 2004).