The TRPC family of TRP channels: roles inferred (mostly) from knockout mice and relationship to ORAI proteins.

Aside from entering into cells through voltage gated Ca channels and Na/Ca exchangers in those cells that express these proteins, for all cells be they excitable or non-excitable, Ca(2+) enters through channels that are activated downstream of phosphoinositide mobilization (activation of phospholipase C, PLC) and through channels that are activated secondary to depletion of internal stores. Depletion of internal stores activates plasma membrane channels known as ORAIs. Activation of PLCs activates the canonical class of transient receptor potential channels (TRPCs), and, because this activation also causes depletion of Ca(2+) stores, also ORAI based channels. Whereas the activation of ORAI is a well-accepted phenomenon, it appears that TRPC channels also participate in Ca(2+) entry triggered by store depletion with or without participation of ORAI molecules. Regardless of molecular makeup of TRPC containing channels, a plethora of studies have shown TRPCs to be important both in physiologic systems as well as in pathophysiologic phenomena. Particularly important in defining roles of TRPCs, have been studies with mice with targeted disruption of their genes, i.e., with TRPC KO mice. In this chapter we first focus on TRPCs as regulators of body functions in health and disease, and then focus on the possible make-up of the channels of which they participate. A hypothesis is set forth, whereby ORAI dimers are proposed to be regulatory subunits of tetrameric TRPC channels and serve as structural units that form ORAI channels either as dimers of dimers or trimers of dimers.