TRPC-mediated Ca2+ signaling and control of cellular functions.

Published on Oct 1, 2019in Seminars in Cell & Developmental Biology5.46
· DOI :10.1016/J.SEMCDB.2019.02.001
Sanja Curcic7
Estimated H-index: 7
(Medical University of Graz),
Romana Schober4
Estimated H-index: 4
(Johannes Kepler University of Linz)
+ 1 AuthorsKlaus Groschner39
Estimated H-index: 39
(Medical University of Graz)
Abstract Canonical members of the TRP superfamily of ion channels have long been recognized as key elements of Ca2+ handling in a plethora of cell types. The emerging role of TRPC channels in human physiopathology has generated considerable interest in their pharmacological targeting, which requires detailed understanding of their molecular function. Although consent has been reached that receptor-phospholipase C (PLC) pathways and generation of lipid mediators constitute the prominent upstream signaling process that governs channel activity, multimodal sensing features of TRPC complexes have been demonstrated repeatedly. Downstream signaling by TRPC channels is similarly complex and involves the generation of local and global cellular Ca2+ rises, which are well-defined in space and time to govern specific cellular functions. These TRPC-mediated Ca2+ signals rely in part on Ca2+ permeation through the channels, but are essentially complemented by secondary mechanisms such as Ca2+ mobilization from storage sites and Na+/Ca2+ exchange, which involve coordinated interaction with signaling partners. Consequently, the control of cell functions by TRPC molecules is critically determined by dynamic assembly and subcellular targeting of the TRPC complexes. The very recent availability of high-resolution structure information on TRPC channel complexes has paved the way towards a comprehensive understanding of signal transduction by TRPC channels. Here, we summarize current concepts of cation permeation in TRPC complexes, TRPC-mediated shaping of cellular Ca2+ signals and the associated control of specific cell functions.
  • References (178)
  • Citations (6)
📖 Papers frequently viewed together
36 Citations
17 Citations
7 Authors (Aisling Minard, ..., Robin S. Bon)
15 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Oleksandra Tiapko (Medical University of Graz)H-Index: 5
#2Niroj Shrestha (Medical University of Graz)H-Index: 5
Last. Klaus Groschner (Medical University of Graz)H-Index: 39
view all 14 authors...
Lipid-gated TRPC channels are highly expressed in cardiovascular and neuronal tissues. Exerting precise pharmacological control over their activity in native cells is expected to serve as a basis for the development of novel therapies. Here we report on a new photopharmacological tool that enables manipulation of TRPC3 channels by light, in a manner independent of lipid metabolism and with higher temporal precision than lipid photopharmacology. Using the azobenzene photoswitch moiety, we modifie...
6 CitationsSource
#1Xiaowei Hou (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 2
#2Shana R. Burstein (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 2
Last. Stephen B. Long (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 17
view all 3 authors...
: The store-operated calcium (Ca2+) channel Orai governs Ca2+ influx through the plasma membrane of many non-excitable cells in metazoans. The channel opens in response to the depletion of Ca2+ stored in the endoplasmic reticulum (ER). Loss- and gain-of-function mutants of Orai cause disease. Our previous work revealed the structure of Orai with a closed pore. Here, using a gain-of-function mutation that constitutively activates the channel, we present an X-ray structure of Drosophila melanogast...
20 CitationsSource
#1Jingjing Duan (NCU: Nanchang University)H-Index: 18
#2Jian Li (NCU: Nanchang University)H-Index: 5
Last. Jin Zhang (NCU: Nanchang University)H-Index: 15
view all 10 authors...
Members of the transient receptor potential (TRP) ion channels conduct cations into cells. They mediate functions ranging from neuronally mediated hot and cold sensation to intracellular organellar and primary ciliary signaling. Here we report a cryo-electron microscopy (cryo-EM) structure of TRPC4 in its unliganded (apo) state to an overall resolution of 3.3 A. The structure reveals a unique architecture with a long pore loop stabilized by a disulfide bond. Beyond the shared tetrameric six-tran...
43 CitationsSource
#1Hussein N. Rubaiy (University of Leeds)H-Index: 10
#2Melanie J. Ludlow (University of Leeds)H-Index: 10
Last. David J. Beech (University of Leeds)H-Index: 51
view all 8 authors...
BACKGROUND AND PURPOSE: The diterpene ester tonantzitlolone (TZL) is a natural product, which displays cytotoxicity towards certain types of cancer cell such as renal cell carcinoma cells. The effect is similar to that of (-)-englerin A, and so, although it is chemically distinct, we investigated whether TZL also targets transient receptor potential canonical (TRPC) channels of the 1, 4 and 5 type (TRPC1/4/5 channels). EXPERIMENTAL APPROACH: The effects of TZL on renal cell carcinoma A498 cells ...
6 CitationsSource
#1Keisuke Motoyama (Daiichi Sankyo)H-Index: 1
#2Tsutomu NagataH-Index: 8
Last. Tomoko SakakuraH-Index: 1
view all 8 authors...
In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp 2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp 3 carbon atoms to increase the molecular complexity, measured by fraction sp 3 (Fsp 3 ). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512 , inhibited TRPC6 with an IC 50 value of 11 nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNa V 1.5 channels...
7 CitationsSource
#1Caroline SunggipH-Index: 6
#2Kakeru Shimoda (National Institutes of Natural Sciences, Japan)H-Index: 3
Last. Motohiro Nishida (Kyushu University)H-Index: 35
view all 9 authors...
Cardiac hypertrophy, induced by neurohumoral factors, including angiotensin II and endothelin-1, is a major predisposing factor for heart failure. These ligands can induce hypertrophic growth of neonatal rat cardiomyocytes (NRCMs) mainly through Ca2+-dependent calcineurin/nuclear factor of activated T cell (NFAT) signaling pathways activated by diacylglycerol-activated transient receptor potential canonical 3 and 6 (TRPC3/6) heteromultimer channels. Although extracellular nucleotide, adenosine 5...
9 CitationsSource
#1Chen Fan (Van Andel Institute)H-Index: 2
#2Wooyoung Choi (Van Andel Institute)H-Index: 3
Last. Wei Lü (Van Andel Institute)H-Index: 3
view all 5 authors...
: The TRPC channels are crucially involved in store-operated calcium entry and calcium homeostasis, and they are implicated in human diseases such as neurodegenerative disease, cardiac hypertrophy, and spinocerebellar ataxia. We present a structure of the full-length human TRPC3, a lipid-gated TRPC member, in a lipid-occupied, closed state at 3.3 Angstrom. TRPC3 has four elbow-like membrane reentrant helices prior to the first transmembrane helix. The TRP helix is perpendicular to, and thus dise...
45 CitationsSource
#1Deivanayagabarathy Vinayagam (MPG: Max Planck Society)H-Index: 1
#1Deivanayagabarathy Vinayagam (MPG: Max Planck Society)H-Index: 1
Last. Stefan Raunser (MPG: Max Planck Society)H-Index: 34
view all 8 authors...
: Canonical transient receptor channels (TRPC) are non-selective cation channels. They are involved in receptor-operated Ca2+ signaling and have been proposed to act as store-operated channels (SOC). Their malfunction is related to cardiomyopathies and their modulation by small molecules has been shown to be effective against renal cancer cells. The molecular mechanism underlying the complex activation and regulation is poorly understood. Here, we report the electron cryo-microscopy structure of...
51 CitationsSource
#1Qinglin Tang (PKU: Peking University)H-Index: 1
#2Wenjun Guo (PKU: Peking University)H-Index: 1
Last. Lei Chen (PKU: Peking University)H-Index: 13
view all 8 authors...
TRPC6 and TRPC3 are receptor-activated nonselective cation channels that belong to the family of canonical transient receptor potential (TRPC) channels. They are activated by diacylglycerol, a lipid second messenger. TRPC6 and TRPC3 are involved in many physiological processes and implicated in human genetic diseases. Here we present the structure of human TRPC6 homotetramer in complex with a newly identified high-affinity inhibitor BTDM solved by single-particle cryo-electron microscopy to 3.8 ...
61 CitationsSource
#1Michaela Lichtenegger (Medical University of Graz)H-Index: 6
#2Oleksandra Tiapko (Medical University of Graz)H-Index: 5
Last. Klaus Groschner (Medical University of Graz)H-Index: 39
view all 14 authors...
Transient receptor potential canonical (TRPC) channels TRPC3, TRPC6 and TRPC7 are able to sense the lipid messenger diacylglycerol (DAG). The DAG-sensing and lipid-gating processes in these ion channels are still unknown. To gain insights into the lipid-sensing principle, we generated a DAG photoswitch, OptoDArG, that enabled efficient control of TRPC3 by light. A structure-guided mutagenesis screen of the TRPC3 pore domain unveiled a single glycine residue behind the selectivity filter (G652) t...
22 CitationsSource
Cited By6
#1Katherine E. Huffer (NIH: National Institutes of Health)H-Index: 3
#2Antoniya A. Aleksandrova (NIH: National Institutes of Health)H-Index: 6
Last. Kenton J. Swartz (NIH: National Institutes of Health)H-Index: 36
view all 5 authors...
The recent proliferation of published TRP channel structures provides a foundation for understanding the diverse functional properties of this family of ion channel proteins. To facilitate mechanistic investigations, we constructed a structure-based alignment of the transmembrane domains of 120 TRP channel structures. Structural comparison reveals similar constrictions in the central ion permeation pathway near the intracellular end of the S6 helices, pointing to a conserved cytoplasmic gate and...
#1Sharon Negri (UNIPV: University of Pavia)H-Index: 5
#2Pawan FarisH-Index: 6
Last. Francesco Moccia (UNIPV: University of Pavia)H-Index: 33
view all 5 authors...
Vasculogenesis, angiogenesis and arteriogenesis represent three crucial mechanisms involved in the formation and maintenance of the vascular network in embryonal and post-natal life. It has long been known that endothelial Ca2+ signals are key players in vascular remodeling; indeed, multiple pro-angiogenic factors, including vascular endothelial growth factor, regulate endothelial cell fate through an increase in intracellular Ca2+ concentration. Transient Receptor Potential (TRP) channel consis...
4 CitationsSource
#1Paula Nunes-Hasler (University of Geneva)H-Index: 4
#2Mayis Kaba (University of Geneva)H-Index: 1
Last. Nicolas Demaurex (University of Geneva)H-Index: 56
view all 3 authors...
: Calcium (Ca2+) is a ubiquitous second messenger involved in the regulation of numerous cellular functions including vesicular trafficking, cytoskeletal rearrangements and gene transcription. Both global as well as localized Ca2+ signals occur during phagocytosis, although their functional impact on the phagocytic process has been debated. After nearly 40 years of research, a consensus may now be reached that although not strictly required, Ca2+ signals render phagocytic ingestion and phagosome...
#1Jonas Weber (LMU: Ludwig Maximilian University of Munich)H-Index: 1
#2Yu-Kai Chao (LMU: Ludwig Maximilian University of Munich)H-Index: 7
Last. Alexander Dietrich (LMU: Ludwig Maximilian University of Munich)H-Index: 44
view all 12 authors...
Ischemia-reperfusion(IR)-induced edema formation can be mimicked ex-vivo in isolated perfused mouse lungs (IPL). Here we show enhanced edema formation in transient receptor potential vanilloid 4 (TRPV4)-deficient (TRPV4-/-) IPL compared to wild-type (WT) controls in response to IR, indicating a protective role of TRPV4 to maintain the alveolar epithelial barrier. By immunohistochemistry, mRNA profiling or electrophysiological analysis we detected TRPV4 in bronchial epithelium, alveolar type I (A...
#1Francesco Moccia (UNIPV: University of Pavia)H-Index: 33
#2Sharon Negri (UNIPV: University of Pavia)H-Index: 5
Last. Germano Guerra (UNIMOL: University of Molise)H-Index: 29
view all 5 authors...
It has long been known that endothelial Ca2+ signals drive angiogenesis by recruiting multiple Ca2+-sensitive decoders in response to pro-angiogenic cues, such as vascular endothelial growth factor, basic fibroblast growth factor, stromal derived factor-1α and angiopoietins. Recently, it was shown that intracellular Ca2+ signaling also drives vasculogenesis by stimulation proliferation, tube formation and neovessel formation in endothelial progenitor cells. Herein, we survey how growth factors, ...
10 CitationsSource
#1J-M ChienH-Index: 1
#2W-Z Liang (Tajen University)H-Index: 1
Last. C-R JanH-Index: 1
view all 7 authors...
Bifenthrin, a commonly used pyrethroid pesticide, evokes various toxicological effects in different models. However, the effect of bifenthrin on cytosolic-free Ca2+ level ([Ca2+]i) and cytotoxicity...
1 CitationsSource