TRPC6

TRPC6 Full Name

transient receptor potential cation channel, subfamily C, member 6

TRPC6 Introduction

TRPC6 belongs to the TRP channel superfamily. It is a non-selective cation channel that is permeable to calcium and sodium ions. When activated, TRPC6 promotes an increase in the intracellular calcium concentration, thus initiating a series of downstream signals. The mode of activation of the TRPC6 channel is complicated and diverse. TRPC6 channel could be modulated by different signaling molecules, for example, can be activated by diacylglycerol (DAG), and can not be activated by endoplasmic reticulum calcium store depletion. Physiologically, TRPC6 is expressed in different tissues and organs in the body, for example, podocyte in kidney, cardiomyocyte in heart, smooth muscle cells in pulmonary arteries, etc. In the above-mentioned cells, TRPC6 is responsible for maintaining normal cell function and tissue homeostasis by fine-tuning calcium influx. For instance, TRPC6 and slit diaphragm proteins (such as nephrin, podocin, etc.) form a functional complex to jointly maintain the glomerular filtration barrier function in the podocyte of the kidney.

Figure 1. Structural features of TRPC6. (Source: Dietrich A, et al. 2014)

TRPC6 dysfunction is highly relevant for the pathogenesis and progression of multiple diseases. Hyperactivation/upregulated expression of TRPC6 channel causes intracellular Ca²⁺ overload and thereby contributes to the occurrence of multiple pathological changes. In kidney diseases, genetic mutation/abnormal expression of TRPC6 is a well-characterized cause of proteinuric nephropathies, such as Focal Segmental Glomerulosclerosis (FSGS). The massive calcium influx into the podocytes results in the damage to podocyte structure and function, such as foot process effacement and cytoskeletal disorder, and eventually leads to the destruction of the glomerular filtration barrier and the development of massive proteinuria. In heart diseases, TRPC6 has been identified as a major inducer of pathological cardiac hypertrophy. Upon pathological stimuli, such as pressure overload, TRPC6 channel is activated and the resulting increased calcium influx facilitates the activation of the downstream calcineurin-NFAT signaling pathway that plays a key role in promoting the hypertrophic growth of cardiomyocytes. In addition, in Pulmonary Arterial Hypertension (PAH), the expression/activity of TRPC6 is significantly upregulated in Pulmonary Arterial Smooth Muscle Cells (PASMCs), which mediates sustained calcium influx and thereby causes excessive proliferation of smooth muscle cells and vascular remodeling that lead to increased pulmonary vascular resistance and high blood pressure.

As TRPC6 is involved in the pathophysiology of some major diseases like kidney disease, heart disease and pulmonary arterial hypertension, it has become a popular target for drug development and TRPC6 inhibitors are proposed to be a promising therapy for the above diseases. For example, in kidney disease models, TRPC6 inhibitors can reduce proteinuria and protect podocytes. In pulmonary arterial hypertension preclinical models, a specific TRPC6 blocker had inhibitory effects on vascular remodeling and ameliorated hemodynamics.

Alternate Names for TRPC6

TRPC6; transient receptor potential cation channel, subfamily C, member 6; TRP6; FSGS2; short transient receptor potential channel 6; TRP-6; transient receptor protein 6; focal segmental glomerulosclerosis 2;

• 1. Dietrich A, et al. TRPC6: physiological function and pathophysiological relevance. Handb Exp Pharmacol. 2014;222:157-88.
  2. Khan SU, et al. The Multifunctional TRPC6 Protein: Significance in the Field of Cardiovascular Studies. Curr Probl Cardiol. 2024 Jan;49(1 Pt B):102112.