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Why TRP channels?

TRP channels form a superfamily of ion channels that allow the regulated passage of cations such as Ca2+, Na+ or Mg2+ across biological membranes. TRP channels are related to the product of the Drosophila trp gene, which forms a cation channel that is involved in light perception in the fly eye. The name TRP refers to the transient response to steady light (transient receptor potential) of trp null-mutant flies, unlike wild-type flies that demonstrate a sustained photoreceptor response.

The human genome contains 27 TRP channel genes, and TRP channel genes have also been identified in various eukaryotic model organisms, ranging from yeast and plants, to worms, insects and vertebrates. The TRP superfamily is subdivided, based on sequence homology, in 7 subfamilies (TRPC, TRPV, TRPM, TRPA, TRPML, TRPP and TRPN).

A functional TRP channel is composed of four subunits that assemble as homo- or sometimes heterotetramers. Each subunit has 6 transmembrane domains, cytosolic N and C termini and a pore loop between transmembrane domains 5 and 6. Transmembrane domains 1-4 and the cytoplasmic parts contain the regulatory domains that control channel gating, as well as phosphorylation sites and binding sites for interacting proteins and ligands.

The functional 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 such as Ca2+, Mg2+, Fe2+ or Zn2+, 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 different 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 detect and integrate different and 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, temperature sensing and vision. 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) or 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 channels have a huge potential as novel therapeutic targets or diagnostic markers.