TRPC3

TRPC3 (and TRPC6) are receptor-activated, non-selective cation channels belonging to the canonical transient receptor potential (TRPC) channel family. They are activated by diacylglycerol (DAG), a lipid second messenger (Hofmann T et al. 1999). TRPC3 is involved in many physiological processes and implicated in human genetic diseases. The high-affinity inhibitor BTDM wedges between the S5-S6 pore domain and the voltage sensor-like domain to inhibit channel opening (Tang Q et al. 2018).

Activation of these channels leads to cell membrane depolarization and calcium influx. TRPC3/6/7 can form either homotetramers or heterotetramers with variable calcium ion permeability. Based on their sequence features, these channels have a tetrameric transmembrane pore that consists of six transmembrane helices, just as in other TRP channels. In addition, they have a large cytoplasmic N-terminus that contains four ankyrin repeats and a C-terminal coiled-coil motif. How these structural elements are incorporated into the tetrameric TRPC channel is largely unknown (Tang Q et al. 2018). In skin, TRPC channels (TRPC1, TRPC3, TRPC4, TRPC5, and TRPC6) are expressed by keratinocytes, where they appear to be involved in the differentiation and proliferation of these cells. Furthermore, TRPC1 and TRPC3 are also expressed in CD4+ T cells, and in neurons of various ganglia. Ganglia.

TRPC3 is also highly expressed in human hypertrophic scar tissue, and mechanical stimuli are known to upregulate TRPC3 expression in human skin fibroblasts in vitro. Animal experiments have shown that mechanical stretching controls fibronectin expression via the TRPC3-NFkB axis, resulting in persistent wound contracture. This model explains how mechanical stretching of skin wounds can lead to pathological scars (Ishise H et al. 2015). Whether TRPC2 plays a role in melanoma cell invasion is currently unclear (Gao J et al. 2018).

TRP channels are phylogenetically early signaling pathways (they can already be detected in yeast cells). The first TRP channel was identified in 1989 in connection with visual perception in Drosophila melanogaster. In a Drosophila mutant (trp343), it was shown that its photoreceptors responded to light stimuli only with a transient, i.e. rapidly inactivating, membrane current. In the non-mutated wild type, however, the current flow persisted as long as light hit the photoreceptor. The mutant protein -TRP- was cloned in 1989. Thus, the name "transient receptor potential" - TRP- refers to the description of a phenotype of a mutant of the fruit fly Drosophila melanogaster. TRP channels exert important functions in primary signaling pathways for the regulated influx of Ca2+ into a cell in both vertebrates and non-vertebrates. TRP channels in humans play an important role in the sensation of different types of taste (sweet, bitter, umami) as well as in the perception of pain, heat, warmth or cold, pressure and light. It is believed that some TRP channels in the body behave like microscopic thermosensors. To date, 28 TRP channel genes have been identified in mammals (Nilius B et al. 2011). The TRPC subfamily consists of seven members (TRPC1-7) known to be non-selective cation channels with permeability to Ca2+, Na+ and K+. Like the other members of the TRP superfamily, they contain six transmembrane domains with an ion channel between the fifth and sixth domains. The N- and C-termini of TRPCs harbor a variety of functional domains including ankyrin repeats, calmodulin binding sites, phosphorylation sites, and sites of interaction with other molecules such as Homer, Orai, STIM1, Junctate, IP3 receptor (IP3R).

1. Gao J et al. (2018) LncRNA SNHG5 promotes growth and invasion in melanoma by regulating the miR-26a-5p/TRPC3 pathway. Onco Targets Ther 12:169-179.
2. Hofmann T et al (1999) Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397: 259-263
3. Ishise H et al (2015) Hypertrophic scar contracture is mediated by the TRPC3 mechanical force transducer via NFkB activation. Sci Rep 25:11620.
4. Nilius B et al (2011) The transient receptor potential family of ion channels. Genome Biol 12:218.
5. Tang Q et al. (2018) Structure of the receptor-activated human TRPC6 and TRPC3 ion channels. Cell Research 28: 746-755