TRPC3

TRPC3 Full Name

transient receptor potential cation channel, subfamily C, member 3

TRPC3 Introduction

TRPC3 is a protein that in humans is encoded by the TRPC3 gene. TRPC3 is a member of the TRP superfamily of cation channels and is classified as a member of the canonical TRPC subfamily. TRPC3 is a non-selective cation channel that is highly permeable to calcium. The TRPC3 protein shares amino acid sequence homology with other TRP proteins, most of the canonical structural characteristics of TRP channels are conserved in TRPC3 including six transmembrane domains (S1-S6), a pore forming loop between S5 and S6, and intracellular N- and C-termini. The TRPC3 channel protein is predicted to contain several important domains for function including N-terminal ankyrin-like repeats, a highly conserved 'TRP box', and a C-terminal calmodulin and IP3 receptor binding domain, all of which are important for channel assembly, localization, and activity. A critical mode of TRPC3 channel activation is direct recognition and activation by the downstream effector diacylglycerol (DAG) from the phospholipase C (PLC) signaling pathway. The DAG binding site has been mapped to a 'L2 site' near the pore region of the channel. Furthermore, calcium may also act as a positive feedback activator of TRPC3 activity. TRPC3 is broadly expressed in most mammalian tissues including the brain (where it is enriched in the cerebellum and striatum), heart, smooth muscle, endothelial cells, and immune cells.

Figure 1. Schematic illustration of the domain structure of TRPC3. (Source: Numaga-Tomita T, et al. 2017)

As a key pathway for calcium influx on the cell membrane, the basic role of TRPC3 is to regulate the intracellular calcium concentration, and then initiate or modulate a series of complex downstream signaling cascades that are involved in various physiological processes. In the nervous system, TRPC3 is necessary for normal neuronal development, synaptic plasticity and electrical activity. For instance, the expression of TRPC3 in the cerebellum is essential for motor coordination, and TRPC3 knockout mice exhibited mild motor ataxia. In the cardiovascular system, TRPC3 is involved in the regulation of vascular tone, endothelial cell function, and normal physiological activity of cardiomyocytes. By mediating calcium influx, TRPC3 can activate a variety of calcium-dependent signaling molecules. The most classical one is the activation of calcineurin, which in turn dephosphorylates its substrate NFAT, so that NFAT can be translocated into the nucleus to initiate the transcription of target genes. The Calcineurin/NFAT signaling pathway is involved in a wide range of physiological and pathological processes, including physiological cardiac hypertrophy, pathological cardiac hypertrophy, and immune cell activation. Calcium signals mediated by TRPC3 can also activate the CaMKII signaling pathway, which is also an important signaling pathway in the heart and nervous system. In addition to the above signaling pathways, TRPC3 also has crosstalk with other signaling molecules and pathways. For instance, it can activate the NF-κB signaling pathway and participate in the regulation of inflammatory responses and immune responses. At the same time, it plays an indispensable role in tissue repair processes such as wound healing, by regulating cell migration, proliferation, and differentiation.

In cardiovascular diseases, pathological cardiac hypertrophy is driven by the abnormal upregulation and overactivation of TRPC3. Chronic calcium influx through TRPC3 inappropriately activates the Calcineurin/NFAT pathway, leading to cardiomyocyte enlargement and pathological hypertrophy, resulting in heart failure. TRPC3 is also involved in hypertension, atherosclerosis and cardiac arrhythmias. In neurodegenerative diseases, TRPC3's function is more complicated. Expression of TRPC3 is upregulated in the brains of AD patients and animal models, and the expression level of TRPC3 correlates significantly with amyloid-β (Aβ) burden. TRPC3 activity inhibition can rescue synaptic function and memory deficits in AD animal models. These results suggested that TRPC3 may be a downstream effector of Aβ's neurotoxicity. Abnormally aggregated α-synuclein in PD models can induce neuronal mitochondria to upregulate TRPC3 expression. TRPC3 expression, in turn, interferes with mitochondrial function, induces apoptosis, and promotes dopaminergic neuronal death. In cancer biology, TRPC3 also plays a pro-tumorigenic role. TRPC3 expression is upregulated in various types of cancers, including ovarian, breast, prostate, and pancreatic cancer, and sustains cancer cell (especially cancer stem cells) proliferation, migration and drug resistance by mediating constitutive calcium influx.

Alternate Names for TRPC3

TRPC3; transient receptor potential cation channel, subfamily C, member 3; TRP3; short transient receptor potential channel 3; hTrp-3; transient receptor protein 3; transient receptor potential cation channel subfamily C member 3 variant c;

• 1. Nishiyama K, et al. TRPC3-Based Protein Signaling Complex as a Therapeutic Target of Myocardial Atrophy. Curr Mol Pharmacol. 2021;14(2):123-131.
  2. Numaga-Tomita T, et al. TRPC3 Channels in Cardiac Fibrosis. Front Cardiovasc Med. 2017 Sep 7;4:56.