TRPCs as MS Channels

This chapter reviews recent evidence indicating that canonical or classical transient receptor potential (TRPC) channels are directly or indirectly mechanosensitive (MS) and can therefore be designated as mechano-operated channels (MOCs). The MS functions of TRPCs may be mechanistically related to their better known functions as store-operated and receptor-operated channels (SOCs and ROCs). Mechanical forces may be conveyed to TRPC channels through the "conformational coupling" mechanism that transmits information regarding the status of internal Ca(2+) stores. All TRPCs are regulated by receptors coupled to phospholipases that are themselves MS and can regulate channels via lipidic second messengers. Accordingly, there may be several nonexclusive mechanisms by which mechanical forces may regulate TRPC channels, including direct sensitivity to bilayer mechanics, physical coupling to internal membranes and/or cytoskeletal proteins, and sensitivity to lipidic second messengers generated by MS enzymes. Various strategies that can be used for separating out different MS-gating mechanisms and their possible role in specific TRPCs are discussed.