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Review
. 2017 Jun 16:8:707.
doi: 10.3389/fimmu.2017.00707. eCollection 2017.

The Role of Transient Receptor Potential Channel 6 Channels in the Pulmonary Vasculature

Monika Malczyk  1 , Alexandra Erb  1 , Christine Veith  1 , Hossein Ardeschir Ghofrani  1 , Ralph T Schermuly  1 , Thomas Gudermann  2 , Alexander Dietrich  2 , Norbert Weissmann  1 , Akylbek Sydykov  1
Affiliations
Review

The Role of Transient Receptor Potential Channel 6 Channels in the Pulmonary Vasculature

Monika Malczyk et al. Front Immunol. .

Abstract

Canonical or classical transient receptor potential channel 6 (TRPC6) is a Ca2+-permeable non-selective cation channel that is widely expressed in the heart, lung, and vascular tissues. The use of TRPC6-deficient ("knockout") mice has provided important insights into the role of TRPC6 in normal physiology and disease states of the pulmonary vasculature. Evidence indicates that TRPC6 is a key regulator of acute hypoxic pulmonary vasoconstriction. Moreover, several studies implicated TRPC6 in the pathogenesis of pulmonary hypertension. Furthermore, a unique genetic variation in the TRPC6 gene promoter has been identified, which might link the inflammatory response to the upregulation of TRPC6 expression and ultimate development of pulmonary vascular abnormalities in idiopathic pulmonary arterial hypertension. Additionally, TRPC6 is critically involved in the regulation of pulmonary vascular permeability and lung edema formation during endotoxin or ischemia/reperfusion-induced acute lung injury. In this review, we will summarize latest findings on the role of TRPC6 in the pulmonary vasculature.

Keywords: hypoxic pulmonary vasoconstriction; pulmonary hypertension; transient receptor potential channel 6; transient receptor potential channels; vascular permeability.

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Figures

Figure 1
Figure 1
[Ca2+]i homeostasis regulation in precapillary pulmonary arterial smooth muscle cells (PASMCs) and ECs. Ca2+ enters cells from extracellular fluid through L-type voltage-dependent calcium channels or non-selective cation channels, which can be divided into SOCCs and ROCCs. The initiation of ROCC-mediated Ca2+-influx from the extracellular space is thought to be induced by ligand-activated G-protein coupled receptors, starting a PLC-mediated hydrolyzation of PIP2 to IP3 and DAG. DAG regulates the activity of ROCC to induce receptor-operated Ca2+ entry, whereas IP3 generation induces depletion of the intracellular Ca2+ stores in the endoplasmic reticulum, leading to induction of store-operated Ca2+ entry. The increased [Ca2+]i drives different cellular responses. Ca2+, calcium ion; [Ca2+]i, intracellular Ca2+ concentration; ROCC, receptor-operated calcium channel; SOCC, store-operated calcium channel; VDCC, L-type voltage-dependent calcium channel; DAG, diacylglycerol; DAGK, DAG kinase; EC, endothelial cell; ER/SR, endoplasmic/sarcoplasmic reticulum; IP3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; L, ligand; PA, phosphatidic acid; PASMC, precapillary pulmonary arterial smooth muscle cells; PIP2, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; VEGF, vascular endothelial growth factor; solid arrows indicate direct interactions; dotted arrows illustrate indirect interactions.
Figure 2
Figure 2
Mechanisms of TRPC6 regulation and function in precapillary pulmonary arterial smooth muscle cells (PASMCs) and ECs in response to hypoxia. The TRPC6 protein forms homomeric and heteromeric channels composed of TRPC6 alone or TRPC6 and other TRPC proteins. TRPC6 is expressed in PASMCs from mice, rat, as well as humans and is suggested to play a significant role in human idiopathic PAH. The initiation of TRPC6-mediated Ca2+ influx from the extracellular space is thought to be induced by ligand-activated G-protein coupled receptors, starting a PLC-mediated hydrolyzation of PIP2 to IP3 and DAG. It has been already shown that DAG activates TRPC6-containing channels to induce Ca2+ influx from the extracellular space. Ca2+ entry through TRPC6 might be triggered by hypoxia-induced O2− production or hypoxia-induced DAG accumulation and that the increased [Ca2+]i drives different cellular responses through ERK and p38, NFAT, and NF-κB downstream signaling. These pathways might be involved in the induction of TRPC6 expression and contribute to the modulated cellular response associated with hypoxia. Moreover, hypoxia leads to acute stabilization of HIF-1α, which might induce TRPC6 expression among other proteins. 11,12 EET, 11,12-epoxyeicosatrienoic acid; Ca2+, calcium ion; [Ca2+]i, intracellular Ca2+ concentration; DAG, diacylglycerol; DAGK, DAG kinase; EC, endothelial cell; ER/SR, endoplasmic/sarcoplasmic reticulum; ERK, extracellular signal-regulated kinase; ET-1, endothelin-1; G, G-protein; H2O2, hydrogen peroxide; HIF-1α, hypoxia-inducible factor 1 alpha; IP3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; L, ligand; NF-κB, nuclear factor kappa-light-chain enhancer of activated B-cells; NFAT, nuclear factor of activated T-cells; NOX2, NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 2; O2−, superoxide; PA, phosphatidic acid; p38, p38 mitogen-activated protein kinase; PASMC, precapillary pulmonary arterial smooth muscle cells; PIP2, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; SOD, superoxide dismutase; TRPC, classical transient receptor potential channel; TRPC6, classical transient receptor potential channel 6; VEGF, vascular endothelial growth factor; solid arrows indicate direct interactions; dotted arrows illustrate indirect interactions. Not all interaction partners have been identified.
Figure 3
Figure 3
Additional TRPC6 signaling pathways in ECs after lung injury. Recruitment of TRPC6 by the indicated factors increases the density of TRPC6 channels at the plasma membrane (left), which open after activation of endothelial receptors (right) and increase endothelial permeability and inflammatory processes inducing endothelial dysfunction. 11,12 EET, 11,12-epoxyeicosatrienoic acid; ASM, acid sphingomyelinase; Ca2+, calcium ion; [Ca2+]i, intracellular Ca2+ concentration; Cav-1, caveolin-1; DAG, diacylglycerol; EC, endothelial cell; G, G-protein; HIF-1α, hypoxia-inducible factor 1 alpha; L, ligand; LPS, lipopolysaccharide; PAF, platelet-activating factor; PTEN, phosphatase and tensin homolog; PIP2, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; TLR4, toll-like receptor 4; TRPC, classical transient receptor potential channel; TRPC6, classical transient receptor potential channel 6; VEGF, vascular endothelial growth factor; solid arrows indicate direct interactions; dotted arrows illustrate indirect interactions. Not all interaction partners have been identified.
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