TRPC4

TRPC4 is the acronym for "Transient Receptor Potential Cation Channel Subfamily C Member 4", which refers to a non-selective cation channel. TRPC4 is encoded in humans by a gene of the same name located on chromosome 13q13.3. TRPC4 belongs to the family of TRPC cation channels, which are non-selective cation channels with permeability to Ca2+, Na+ and K+. The protein complex forms a non-selective calcium permeable cation channel that is activated by G-coupled receptors and tyrosine kinases. Channel activation leads to cell membrane depolarization followed by an increase in intracellular Ca2+ levels. TRPC4 has been shown to interact with TRPC1 and TRPC5 in the formation of channel structures.

TRPC4 and TRPC5 channels share many functional properties. Both channels exhibit similar current-voltage relationships (Kim H et al. 2012).

The role of TRPC4 as a store-operated channel (SOC) has been demonstrated several times (Wang et al. 2004). Here, two key proteins, calmodulin (CaM) and inositol 1,4,5-triphosphate receptor (IP3R), compete for the same binding site on TRPC4.

Tissue expressions: TRPC4 mRNA is detected in midbrain dopaminergic neurons and substantia nigra (Cooper D et al. 2012). This cation channel has been shown to be required for neurite outgrowth and its expression is upregulated during axonal regeneration after nerve injury. Furthermore, TRPC4 is expressed in smooth muscle cells, endometrium of female reproductive organs and in males in seminal vesicles, prostate (Human Protein Atlas Information 2020). TRPC4 and TRPC5 channels are important regulators of electrical excitability in both gastrointestinal myocytes and neurons. 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. However, the regulation of TRPC channel activity is complex, ranging from modulation by endogenous and dietary lipids to surface receptors, the redox environment, and various types of cations (Jeon et al. 2012). TRPC4 interacts with several proteins that can modulate its activity. These include the ER-resident calcium sensor Stim1, the lipid-binding protein SESTD1, and the G protein Gαi2 (Jeon et al. 2012; Lee et al. 2010; Miehe et al.). Endothelial cells also express TRPC4 channels. There, they are considered key determinants of endothelial Ca2+ signaling and endothelial functions, such as nitric oxide release and barrier stability (Freichel M et al. 2001). Apparently, TRPC4 has an important role in endothelial proliferation (Abdullaev IF et al.2008).

It has been repeatedly shown that TRPC4 is important for the integrity of cell-cell junctions and barrier functions of endothelia ( Cioffi DL et al. 2006).

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). 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).

TRPC4 appears to play a role in the regulation of social phobias. However, deletion of the TRPC4 gene does not appear to affect basic or complex strategic learning. Because the TRPC4 gene is expressed in a select population of midbrain dopamine neurons, it is likely that it plays an important role in dopamine-related processes such as addiction and attention. Single nucleotide polymorphisms in the TRPC4 gene may be associated with generalized epilepsy with photosensitivity (von Spiczak S et al. 2010). Due to their implication in various diseases, TRPC channels also represent a major target for pharmacological intervention by small molecules (Minard et al. 2018). Activation of the channels by the natural product (-)-englerinA (EA), which has high potency and selectivity for TRPC4/5, inhibits tumor growth of renal cancer cells by increasing Ca2+ influx (Akbulut et al. 2015). Other activators include riluzole, BTD, and the glucocorticoid methylprednisolone (Beckmann et al. 2017).

Inhibitors of TRPC4/5 are mostly used to treat renal diseases such as focal segmental glomerulosclerosis (FSGS) (Mundel et al. 2019). Other agents are currently undergoing clinical trials.

Recently, a new class of small-molecule modulators has been identified that are selective for TRPC4/5 and are built on a piperazinone/pyridazinone scaffold (Yu et al. 2019).

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