Biomembranes surround all living cells and delineate the various intracellular organelles of eukaryotic cells. The basic structural unit of all biomembranes is a bilayer of phospholipids, which in its pure form is virtually impermeable to biologically important ions. The regulated transport of ions across biomembranes is achieved through specific ion transport proteins, which include ATP-powered pumps, transporters and channels. Ion channels are protein-based pores across biomembranes that open in response to a specific stimulus and thus allow the passage of specific ions down their electrochemical gradient. The ion fluxes through channels form the basis of rapid electrical signalling in the nervous system and other excitable cell types, mediate the swift changes in intracellular Ca2+ that provoke muscle contraction or hormone release, and are crucially involved in numerous other biological processes. The human genome encodes several hundreds of ion channels, with strongly divergent properties and physiological roles.
Figure 1: Phylogenetic tree of human TRP channels. Note that TRPC2 is not expressed in humans, and that TRPN's only occur in invertebrates
TRPLe focuses on one specific superfamily of cation channels, the TRP channels. These channels are related to the product of the Drosophila trp gene (for transient receptor potential), which forms a cation channel that is involved in light perception in the fly eye. The human genome contains 27 TRP channel genes, and TRP channel genes have also been identified in various eukaryotic model organisms. The TRP superfamily is subdivided, based on sequence homology, in 7 subfamilies (Figure 1). The properties of TRP channels, even within a subfamily, can differ enormously. First, there is a striking diversity in the pore permeability of TRP channels: some are highly selective for divalent cations, others are non-selective for mono- and divalent cations, and still others are only permeable to monovalent cations. Second, there is a daunting variety of stimuli that can regulate the opening/closing (gating) of the TRP channels, such as physical stimuli (temperature, voltage, mechanical stress), exogenous ligands, intracellular cations and lipid components of the plasma membrane. In many instances, a single TRP channel is able to integrate divergent types of stimuli, thus acting as a polymodal sensor.
In accordance with this functional diversity, TRP channels are implicated in a multitude of physiological processes, ranging from Ca2+ and Mg2+ homeostasis and regulation of the vascular tone to bone development, taste perception and temperature sensing. The importance of TRP channels in human health and disease is illustrated by the growing number of monogenic human diseases that are caused by mutations in TRP channel genes, such as hypomagnesemia with secondary hypocalcemia (loss-of-function mutations in TRPM6), autosomal dominant brachyolmia (gain-of-function mutations in TRPV4), autosomal dominant focal segmental glomerulosclerosis (gain-of-function mutations in TRPC6). In addition, TRP channels are implicated in complex pathophysiological conditions including neuropathic pain, cancer, asthma, urinary incontinence and cardiac hypertrophy. Therefore, TRP channel have a huge potential as novel therapeutic targets or diagnostic markers. However, at this point, the development of novel TRP channel-based therapies is held back by the incomplete understanding of the molecular modus operandi of TRP channels, and of their cellular regulation and involvement in normo- and pathophysiology.