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Review
. 2015 Feb 1;308(3):H157-82.
doi: 10.1152/ajpheart.00457.2014. Epub 2014 Nov 21.

Role of TRP channels in the cardiovascular system

Zhichao Yue  1 , Jia Xie  1 , Albert S Yu  1 , Jonathan Stock  1 , Jianyang Du  1 , Lixia Yue  2
Affiliations
Review

Role of TRP channels in the cardiovascular system

Zhichao Yue et al. Am J Physiol Heart Circ Physiol. .

Abstract

The transient receptor potential (TRP) superfamily consists of a large number of nonselective cation channels with variable degree of Ca(2+)-permeability. The 28 mammalian TRP channel proteins can be grouped into six subfamilies: canonical, vanilloid, melastatin, ankyrin, polycystic, and mucolipin TRPs. The majority of these TRP channels are expressed in different cell types including both excitable and nonexcitable cells of the cardiovascular system. Unlike voltage-gated ion channels, TRP channels do not have a typical voltage sensor, but instead can sense a variety of other stimuli including pressure, shear stress, mechanical stretch, oxidative stress, lipid environment alterations, hypertrophic signals, and inflammation products. By integrating multiple stimuli and transducing their activity to downstream cellular signal pathways via Ca(2+) entry and/or membrane depolarization, TRP channels play an essential role in regulating fundamental cell functions such as contraction, relaxation, proliferation, differentiation, and cell death. With the use of targeted deletion and transgenic mouse models, recent studies have revealed that TRP channels are involved in numerous cellular functions and play an important role in the pathophysiology of many diseases in the cardiovascular system. Moreover, several TRP channels are involved in inherited diseases of the cardiovascular system. This review presents an overview of current knowledge concerning the physiological functions of TRP channels in the cardiovascular system and their contributions to cardiovascular diseases. Ultimately, TRP channels may become potential therapeutic targets for cardiovascular diseases.

Keywords: Ca2+ signaling; TRP channels; heart diseases; pathogenesis; vascular disorders.

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Figures

Fig. 1.
Fig. 1.
A phylogenetic tree of human, Zebrafish, and Drosophila transient receptor potential (TRP) channels. Sequence homology analyses show that all TRP channels fall into 7 subfamilies that comprise proteins with distinct channel properties. Because human TRPC2 is a pseudogene, mTRPC2 (mouse) is used for analysis. Aligned by ClustalW, the phylegenic tree was generated according to Jukes-Cantor Genetic Distance Model, and the tree was built by the Neighbor-Joining method. All calculation was done in Geneious software. h, homo sapiens; dr, Danio rerio; dm, Drosophila melanogaster. The TRP subfamilies are represented by different colors. Gene accession numbers are shown as follows: 1) Human TRP channels: canonical TRP (TRPC): hTRPC1 (EAW78963), hTRPC3 (NP_001124170), hTRPC4 (AAI04726), hTRPC5 (EAX02630), hTRPC6 (AAH93660), hTRPC7 (AAI28186); mTRPC2 (NP_001103367); vanilloid TRP (TRPV): hTRPV1 (NP_542437), hTRPV2 (NP_057197), hTRPV3 (NP_001245134), hTRPV4 (NP_067638), hTRPV5 (NP_062815), hTRPV6 (NP_061116); melastatin TRP (TRPM): hTRPM1 (NP_001238949), hTRPM2 (NP_003298), hTRPM3 (Q9HCF6), hTRPM4 (NP_060106), hTRPM5 (NP_055370), hTRPM6 (NP_060132), hTRPM7 (NP_060142), hTRPM8 (NP_076985); polycystic (TRPP): hTRPP2 (NP_000288), hTRPP3 (NP_057196), hTRPP5 (NP_055201); hTRPML1 (NP_065394), hTRPML2 (NP_694991), hTRPML3 (NP_060768); ankyrin TRP (TRPA): hTRPA1(NP_015628). 2) Zebrafish TRP channels: TRPC: drTRPC1 (AGW27444), drTRPC2a (AGW27445), drTRPC3 (AGW27447), drTRPC4a (AGW27448), drTRPC5a (AGW27450), drTRPC6a (AGW27452), drTRPC7a (AGW27454); TRPV: drTRPV1 (NP_001119871), drTRPV4 (NP_001036195), drTRPV6 (NP_001001849); TRPM: drTRPM1a (AGS55979), drTRPM2 (AGS55981), drTRPM3 (AGS55982), drTRPM4a (AGS55983), drTRPM5 (AGS55987), drTRPM6 (AGS55988), drTRPM7 (AGS55989); mucolipin TRP (TRPML): drTRPML1 (AAH54127), drTRPML2 (NP_957442); TRPA: drTRPA1 (NP_001007066); TRPP: drPKD2 (NP_001002310); TRPN: drTRPN (NP_899192). 3) Drosophila TRP channels (74): TRPC: dmTRP (NP_476768), dmTRPL (AAF58904), dmTRP γ (AAF53548); TRPV: dmTRPV_(NANCHUNG) (AAF49752), dmTRPV_(CG4536) (AAF46203); TRPM: dmTRPM (a) (NP_001137672); TRPML: dmTRPML (NP_649145); TRPN: dmTRPN (AAF52248); TRPA: dmTRPA1 (NP_476768), dm pain (AAF47293), dmwtrw (AHN57213), dmpyx (AAF47356); TRPP: dmTRPP1 (NP_609561).
Fig. 2.
Fig. 2.
Predicted structural topology of TRP channels. All TRP channels contain 6 transmembrane segments (S1 to S6) with a putative pore region (P) between S5 and S6. NH2- and COOH-termini are variable in length and contain different sets of domains. There are 4, 3, and 14 ankryrin (Ank) repeats in the TRPC subfamily, TRPV subfamily, and TRPA1, respectively. The NH2 terminus of TRPMs is characterized by 4 stretches of residues, designated as the TRPM homology domain (MHD). The TRP domain (TRP-D) is present in the members of the TRPC and TRPM subfamilies. An enzyme domain is present in some of the channels, e.g., TRPM2 has an ADP-ribose pyrophosphatase, whereas TRPM6 and TRPM7 contain an atypical protein kinase. TRPP2 interacts with TRPP1, the 11-transmembrane protein, to form a channel complex.
Fig. 3.
Fig. 3.
Schematic diagram of regulation of TRP channels by phospholipids and lipid rafts. TRP channels can be modulated by various phospholipids, including arachidonic acid (AA) generated by PLA2, phosphatidylinositol 4,5-bisphosphate (PIP2), and lipids in the lipid rafts. AA can be metabolized through 3 enzymatic pathways: 1) the cyclooxygenase (COX) pathway produces prostaglandins; 2) the lipoxygenase (LOX) pathway yields monohydroxy compounds and leukotrienes; and 3) the cytochrome P-450 (CYP) epoxygenase pathway generates hydroxyleicosatetraenoic acids (HETES) and epoxyeicosatrienoic acids (EETs). PIP2 is a co-activator of many TRP channels. Diaglycerol (DAG) generated by hydrolyzing PIP2 via Gq-linked receptor stimulation activates TRPC3 and TRPC6. Lipid rafts are specific microdomains orchestrating various signaling pathways, including GPCR, ion channels, and caveolin-1 (endothelial cells), or caveolin-3 (myocytes). Caveolae are a special type of lipid raft. Lipid rafts are enriched with cholesterol and sphingolipids. Disruption of lipid rafts by depletion of cholesterol or knockdown of caveolin alters TRP channel function within the rafts. Modified from Yue et al. (359).
Fig. 4.
Fig. 4.
Proposed mechanism underlying cardiac hypertrophy via TRPC/calcineurin/Nuclear factor of activated T-cells (NFAT) pathway. Activation of Gq-linked receptors by hypertrophic stimuli, such as ANG II, phenylephrine (PE), and endothelial-1 (ET-1), leads to the production of DAG and IP3 via hydrolysis of PIP2 by PLC activation. DAG activates TRPC3 and TRPC6, and IP3-induced store depletion releases Ca2+ and subsequently activates TRPC channels. The resultant rise in [Ca2+]i activates calcineurin (Cn) and causes translocation of NFAT, leading to the activation of hypertrophic gene expression, including TRPC1, 3, and 6. Upregulated TRPC channels will further activate the Cn/NFAT pathway, thereby perpetuating the TRPC-Ca2+-Cn/NFAT hypertrophy cascade (69, 151, 325).
Fig. 5.
Fig. 5.
Localization of the identified mutations in the TRPM4 channel. Mutations resulting in cardiac conduction defect are in green; mutations identified in Brugada syndrome (BrS) are in blue; and mutations identified in both are in yellow (147, 172, 173, 280). There are also 8 polymorphisms (not shown), including A101T, Y103C, R252H, K487-L498del, D561A, R762-G765del, Q854R, and P1204L identified in BrS, right bundle branch block, and control individuals (280). Modified from Stallmeyer et al. (280).
Fig. 6.
Fig. 6.
TRP channels and heart diseases associated with cardiac fibrosis. Several TRP channels, including TRPC3, TRPC6, TRPV4, TRPM2, and TRPM7, are functionally expressed in cardiac fibroblasts. Different TRP channels are activated when fibroblasts are stimulated by different stimuli, and mediate Ca2+ entry to support fibroblast proliferation, differentiation to myofibroblasts, and synthesis of extracellular matrix proteins and cytokines. Cytokines will in turn stimulate fibroblasts/myofibroblasts to perpetuate the fibrogenesis cascade. Fibrosis is the results of excessive extracellular matrix protein deposition, which contributes to the pathogenesis of various diseases, such as arrhythmia, hypertrophy, and heart failure.
Fig. 7.
Fig. 7.
Role of TRP channels in the vascular system. A: TRP channels expressed in endothelial cells (ECs) and smooth muscle cells (SMCs) are involved in various functions of ECs and SMCs, including vasorelaxation, vasoconstriction, endothelial permeability, myogenic tone regulation, and SMC proliferation. B: schematic diagram illustrating endothelium-dependent vasorelaxation, and agonists as well as stretch/pressure-induced vasoconstriction. Activation of TRPV4 or other TRP channels in ECs by shear stress induces vasorelaxation through at least 2 pathways: 1) Ca2+ entry-mediated by TRPV4 activates SKCa and IKCa, leading to hyperpolarization of ECs and relaxation of SMCs through myoendothelial coupling (gap junctions); 2) Ca2+ influx via TRP channels in ECs enhances the synthesis and release of vasodilator factors such as nitric oxide (NO), which can inhibit voltage-gated Ca2+ channels (VGCC) and TRPC6 via cGMP-dependent pathway to induce relaxation. In SMCs, TRPV4 activation by EETs or other agonists triggers SR Ca2+ release and activation of BKCa, leading to hyperpolarization and vasorelaxation. Activation of TRPC channels such as TRPC6 or TRPC3 in SMCs via Gq-linked GPCRs stimulation by agonists (ANG II, ET-1, or PE) causes depolarization, and subsequent activation of VGCC leading to vasoconstriction. Moreover, stretch or pressure-induced activation of TRP channels, such as TRPM4 and TRPP2, can also depolarize SMCs, resulting in vasoconstriction.
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