On the potential role of source and species of diacylglycerol in phospholipase-dependent regulation of TRPC3 channels

Members of the Transient receptor Potential Canonical (TRPC) family of channel forming proteins are among the most important Ca2+-permeable cation channels in non-excitable cells. Physiologically, TRPC channels are activated downstream receptor-dependent stimulation of phospholipases, either by store-operated or non-store operated mechanisms. TRPC3, a member of the TRPC3/6/7 subfamily, has been largely studied mostly due to its ability to function in one or the other modes, depending on cell type and expression conditions. The role of TRPC3 as a non-store operated channel has been attributed to its ability to respond to diacylglycerol (DAG) either exogenously applied or endogenously produced following activation of receptor-stimulated phospholipases. Despite the vast amount of information accumulated on this topic, some critical aspects related to phospholipase-dependent DAG-mediated regulation of TRPC3 remain unclear and/or unexplored. Among these, the source and species of native DAG, modulation by different DAG-generating phospholipases and protein kinase C-dependent inhibition of TRPC3 in its native environment are just few examples. The present essay is intended to compile existing knowledge on the nature of phospholipase-derived DAGs, their biophysical properties and current evidence on phospholipase-dependent regulation of TRPC3, to speculate on potential scenarios that may eventually provide answers to some of the above questions.