Alternative titles; symbols
HGNC Approved Gene Symbol: TRPC5
Cytogenetic location: Xq23 Genomic coordinates (GRCh38) : X:111,768,011-112,082,776 (from NCBI)
Calcium influx across the plasma membrane evokes diverse cellular responses, ranging from the regulation of gene expression to the release of neurotransmitter. A Drosophila mutant, termed 'transient receptor potential' (trp), has provided insight into the molecular basis of receptor-activated calcium entry into cells. TRPC5 is 1 of several mammalian trp homologs (summary by Sossey-Alaoui et al., 1999).
By sequencing random clones from Xq23 and searching a sequence database, Sossey-Alaoui et al. (1999) identified a cDNA encoding TRPC5, a potential calcium channel protein. The predicted 973-amino acid TRPC5 protein has a calculated molecular mass of 111.5 kD. It contains the characteristic 8 predicted transmembrane domains (TM1 through TM8), including a pore region (TM7) between TM6 and TM8. The N-terminal cytoplasmic region has 2 putative ankyrin motifs and 2 conserved potential cAMP- and cGMP-dependent protein kinase phosphorylation sites. The C-terminal cytoplasmic region has another potential cAMP-and cGMP-dependent protein kinase phosphorylation site and a VTRRL motif, which resembles the PDZ domain interaction site of other ion channels. Human TRPC5 shares 97% amino acid identity with mouse Trp5 and 99% identity with a rabbit TRP, Cce2. Together with bovine Trp4, these proteins form a subbranch of the TRP superfamily. Northern blot analysis detected a TRPC5 transcript of more than 9.5 kb that was expressed mostly in brain, with higher levels in fetal rather than adult brain. The level of expression was higher in cerebellum, cerebral cortex, occipital pole, and frontal lobe than in other brain regions. A 3.2-kb transcript was also found in adult pancreas.
By immunohistochemical analysis, Lau et al. (2016) found that Trpc5 was expressed in somata of sensory neurons in rat left nodose ganglion, in peripheral axons of these neurons in aortic depressor nerve, and in baroreceptor terminals that innervate aortic arch adventitia. Trpc5 expression was found in myelinated and some unmyelinated axon fibers. Trpc5 was expressed on the surface of nonpermeabilized baroreceptor neurons.
Sossey-Alaoui et al. (1999) determined that the TRPC5 gene spans over 300 kb and contains 11 exons.
By YAC analysis, Sossey-Alaoui et al. (1999) mapped the TRPC5 gene to Xq23, a region where several disorders have been localized, including nonsyndromic X-linked mental retardation (XLMR). Although the authors failed to identify a disease-causing mutation in the TRPC5 gene in several XLMR families, they considered it a candidate gene for other disorders mapped to Xq23.
Strubing et al. (2001) demonstrated that TRPC1 (602343) and TRPC5 are subunits of a heteromeric neuronal channel in mammalian brain. Using immunostaining to characterize the expression pattern of rat TRPC1, they concluded that TRPC1 and TRPC5 proteins have overlapping distributions in the hippocampus. Coexpression of TRPC1 and TRPC5 in cells resulted in a novel nonselective cation channel with a voltage dependence similar to NMDA receptor channels. TRPC1/TRPC5 heteromers were activated by Gq-coupled receptors independent of calcium store depletion. Strubing et al. (2001) proposed that many TRPC heteromers form diverse receptor-regulated nonselective cation channels in the mammalian brain.
Using immunohistochemistry, Greka et al. (2003) showed that the TRPC5 protein was present in hippocampal neuronal growth cones, neuronal cell bodies, areas consistent with new synapse formation, and cytoplasmic transport vesicles along neuronal processes. TRPC5 colocalized with stathmin-like-2 (600621), a neuronal growth protein, within the vesicles and in the growth cone. A dominant-negative form of TRPC5 allowed significantly longer neurites and filopodia to form, suggesting that TRPC5 regulates neuronal growth. Greka et al. (2003) noted that influxes of calcium via voltage-gated channels play a role in neuronal outgrowth and suggested that TRPC5 is a candidate for the regulation of calcium waves.
Xu et al. (2008) showed the activation of TRPC5 homomultimeric and TRPC5-TRPC1 (602343) heteromultimeric channels by extracellular reduced thioredoxin, which acts by breaking a disulfide bridge in the predicted extracellular loop adjacent to the ion selectivity filter of TRPC5. Thioredoxin is an endogenous redox protein with established intracellular functions, but it is also secreted. Particularly high extracellular concentrations of thioredoxin are apparent in rheumatoid arthritis (180300), an inflammatory joint disease that disables millions of people worldwide. Xu et al. (2008) showed that TRPC5 and TRPC1 are expressed in secretory fibroblast-like synoviocytes from patients with rheumatoid arthritis, that endogenous TRPC5-TRPC1 channels of the cells are activated by reduced thioredoxin, and that blockade of the channels enhances secretory activity and prevents the suppression of secretion by thioredoxin. Xu et al. (2008) concluded that their data indicate the presence of a previously unrecognized ion channel activation mechanism that couples extracellular thioredoxin to cell function.
Using patch-clamp recording with blocking antibodies and dominant-negative constructs, Lau et al. (2016) identified Trpc5 as the major stretch-activated channel in mouse and rat aortic baroreceptor somata and neurite terminals. The current-voltage relationship of hypoosmolarity-activated currents displayed double rectification typical of Trpc5, which was blocked by Trpc5-inactivating antibodies.
RAC1 (602048) induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Zhou et al. (2017) identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of this inhibitor suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of focal segmental glomerulosclerosis (FSGS; see 603278). The inhibitor also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. Zhou et al. (2017) concluded that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.
In a boy with intellectual disability, Mignon-Ravix et al. (2014) identified a hemizygous 47-kb deletion in Xq23 involving the first exon of the TRPC5 gene. The patient had macrocephaly, delayed psychomotor development, speech delay, behavioral problems, and autistic features. There were no dysmorphic features. The deletion was also found in the unaffected mother who had random X-chromosome inactivation in her lymphocytes. Functional studies of the variant and studies on patient cells were not performed. The patient was ascertained from a cohort of 54 males with X-linked intellectual disability who were analyzed by array CGH.
Lau et al. (2016) found that lentivirus-mediated disruption of Trpc5 in rat reduced pressure-induced sensitivity and spike frequency in baroreceptor neurons. Relative to controls, Trpc5 -/- mice had elevated resting blood pressure, larger variations in mean arterial pressure during a 24-hour recording period, and more modest baroreflex-mediated reduction in heart rate following intraperitoneal phenylephrine injection. Stretch- and pressure-activated channel activity was reduced in isolated Trpc5 -/- mouse aortic baroreceptor neurons.
Blum et al. (2019) found that Trpc5 was expressed in tyrosine hydroxylase (TH; 191290)-positive neurons of arcuate nucleus (ARC) in mice. Loss of Trpc5 function, either genetically or through pharmacologic blockade, caused severe consequences for firing activity in Th-positive ARC neurons, as Trpc5-deficient Th-positive ARC neurons lacked stabilized infraslow oscillatory activity and lost prolactin-evoked excitation. These abnormalities resulted in altered reproductive cyclicity, hypoprolactinemia, and hormonal imbalance in female mice, leading to impaired reproductive capabilities.
Blum, T., Moreno-Perez, A., Pyrski, M., Bufe, B., Arifovic, A., Weissgerber, P., Freichel, M., Zufall, F., Leinders-Zufall, T. Trpc5 deficiency causes hypoprolactinemia and altered function of oscillatory dopamine neurons in the arcuate nucleus. Proc. Nat. Acad. Sci. 116: 15236-15243, 2019. [PubMed: 31285329] [Full Text: https://doi.org/10.1073/pnas.1905705116]
Greka, A., Navarro, B., Oancea, E., Duggan, A., Clapham, D. E. TRPC5 is a regulator of hippocampal neurite length and growth cone morphology. Nature Neurosci. 6: 837-845, 2003. [PubMed: 12858178] [Full Text: https://doi.org/10.1038/nn1092]
Lau, O.-C., Shen, B., Wong, C.-O., Tjong, Y.-W., Lo, C.-Y., Wang, H.-C., Huang, Y., Yung, W.-H., Chen, Y.-C., Fung, M.-L., Rudd, J. A., Yao, X. TRPC5 channels participate in pressure-sensing in aortic baroreceptors. Nature Commun. 7: 11947, 2016. Note: Electronic Article. Erratum: Nature Commun. 9: 16184, 2018. [PubMed: 27411851] [Full Text: https://doi.org/10.1038/ncomms11947]
Mignon-Ravix, C., Cacciagli, P., Choucair, N., Popovici, C., Missirian, C., Milh, M., Megarbane, A., Busa, T., Julia, S., Girard, N., Badens, C., Sigaudy, S., Philip, N., Villard, L. Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes. Am. J. Med. Genet. 164A: 1991-1997, 2014. [PubMed: 24817631] [Full Text: https://doi.org/10.1002/ajmg.a.36602]
Sossey-Alaoui, K., Lyon, J. A., Jones, L., Abidi, F. E., Hartung, A. J., Hane, B., Schwartz, C. E., Stevenson, R. E., Srivastava, A. K. Molecular cloning and characterization of TRPC5 (HTRP5), the human homologue of a mouse brain receptor-activated capacitative Ca(2+) entry channel. Genomics 60: 330-340, 1999. [PubMed: 10493832] [Full Text: https://doi.org/10.1006/geno.1999.5924]
Strubing, C., Krapivinsky, G., Krapivinsky, L., Clapham, D. E. TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron 29: 645-655, 2001. [PubMed: 11301024] [Full Text: https://doi.org/10.1016/s0896-6273(01)00240-9]
Xu, S.-Z., Sukumar, P., Zeng, F., Li, J., Jairaman, A., English, A., Naylor, J., Ciurtin, C., Majeed, Y., Milligan, C. J., Bahnasi, Y. M., Al-Shawaf, E., Porter, K. E., Jiang, L.-H., Emery, P., Sivaprasadarao, A., Beech, D. J. TRPC channel activation by extracellular thioredoxin. Nature 451: 69-72, 2008. [PubMed: 18172497] [Full Text: https://doi.org/10.1038/nature06414]
Zhou, Y., Castonguay, P., Sidhom, E.-H., Clark, AR., Dvela-Levitt, M., Kim, S., Sieber, J., Wieder, N., Jung, J. Y., Andreeva, S., Reichardt, J., Dubois, F., and 9 others. A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science 358: 1332-1336, 2017. [PubMed: 29217578] [Full Text: https://doi.org/10.1126/science.aal4178]