The research group of Chen Lei from Future Institute of Technology reports the mechanism of intracellular calcium ion regulation of TRPC3/6 channels

The classical transient receptor potential channel TRPC is a non-selective cation channel permeable to calcium ions ¹ , with the highest sequence similarity to the TRP channel first discovered in the Drosophila photoreceptor system ^2,3 , and can be used by second messengers.

On January 19, 2022, the research group of Chen Lei, Institute of Molecular Medicine, School of Future Technology, Peking University, Peking University-Tsinghua Life Science Joint Center , reported the structural mechanism of Ca ²⁺ regulation of human TRPC3/6 and FSGS-related mutations in Neuron .

In the process of studying TRPC3/6 channels, the authors used the inside-out patch-clamp technique to find that Ca ²⁺ on the cytoplasmic side can inhibit the background current of TRPC3 channel, while the background current of TRPC6 channel shows a low concentration of activation high The phenomenon of concentration inhibition

The structure shows that the TRPC6 GOF point mutations found in FSGS disease are distributed at the interface of the interaction between the subunits of the intracellular domain, which may disrupt the interaction between the subunits

Finally, the authors solved the high-resolution structure (2.

In conclusion, through structural analysis and functional verification, this study confirmed that the TRPC3/6 channel has an inhibitory Ca ²⁺ binding site CBS1 in the cytoplasmic region

Figure 1.

The first author of this study is Guo Wenjun, a doctoral student at the Institute of Molecular Medicine, School of Future Technology, Peking University; doctoral students Tang Qinglin, Wei Miao, postdoctoral fellows Kang Yunlu and Wu Jingxiang participated in some experiments; and researcher Chen Lei is the corresponding author

The laboratory of Chen Lei, Institute of Molecular Medicine, School of Future Technology, Peking University mainly studies the working mechanism of membrane proteins, especially important membrane proteins related to metabolic diseases and cardiovascular diseases ( http:// /rcdw/34142.

1 Feng, S.

2 Wes, PD et al.

3 Zhu, X.

4 Guo, W.

5 Boulay, G.

6 Hartmann, J.

7 Hartmann, J.

8 Jia, Y.
, Zhou, J.
, Tai, Y.
& Wang, Y.
TRPC channels promote cerebellar granule neuron survival.
Nat.
Neurosci.
10, 559-567, doi:10.
1038/nn1870 (2007).

9 Zhou, J.
et al.
Critical role of TRPC6 channels in the formation of excitatory synapses.
Nat.
Neurosci.
11, 741-743, doi:10.
1038/nn.
2127 (2008).

10 Chen, X.
, Sooch, G.
, Demaree, IS, White, FA & Obukhov, AG Transient Receptor Potential Canonical (TRPC) Channels: Then and Now.
Cells9, doi:10.
3390/cells9091983 (2020).

11 Reiser, J.
et al.
TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function.
Nat.
Genet.
37, 739-744, doi:10.
1038/ng1592 (2005).

12 Winn, MP et al.
A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis.
Science308, 1801-1804, doi:10.
1126/science.
1106215 (2005).

13 Mio, K.
et al.
The TRPC3 channel has a large internal chamber surrounded by signal sensing antennas.
J.
Mol.
Biol.
367, 373-383, doi:10.
1016/j.
jmb.
2006.
12.
043 (2007).

14 Fan, C.
, Choi, W.
, Sun, W.
, Du, J.
& Lu, W.
Structure of the human lipid-gated cation channel TRPC3.
Elife7, doi:10.
7554/eLife.
36852 (2018).

15 Tang, Q.
et al.
Structure of the receptor-activated human TRPC6 and TRPC3 ion channels.
Cell Res.
28, 746-755, doi:10.
1038/s41422-018-0038-2 (2018).

16 Bai, Y.
et al.
Structural basis for pharmacological modulation of the TRPC6 channel.
Elife9, e53311, doi:10.
7554/eLife.
53311 (2020).

17 Kamouchi, M.
et al.
Properties of heterologously expressed hTRP3 channels in bovine pulmonary artery endothelial cells.
J Physiol518 Pt 2, 345-358, doi:10.
1111/j.
1469-7793.
1999.
0345p.
x (1999).

18 Lintschinger, B.
et al.
Coassembly of Trp1 and Trp3 proteins generates diacylglycerol- and Ca2+-sensitive cation channels.
J.
Biol.
Chem.
275, 27799-27805, doi:10.
1074/jbc.
M002705200 (2000).

19 Shi, J.
et al.
Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed in HEK293 cells.
J Physiol561, 415-432, doi:10.
1113/jphysiol.
2004.
075051 (2004).

20 Zhang, Z.
et al.
Activation of Trp3 by inositol 1,4,5-trisphosphate receptors through displacement of inhibitory calmodulin from a common binding domain.
Proc.
Natl.
Acad.
Sci.
USA98, 3168-3173, doi:10.
1073/ pnas.
051632698 (2001).

21 Zitt, C.
et al.
Expression of TRPC3 in Chinese hamster ovary cells results in calcium-activated cation currents not related to store depletion.
J.
Cell Biol.
138, 1333-1341, doi:10.
1083/jcb.
138.
6.
1333 ( 1997).

22 Boulay, G.
Ca(2+)-calmodulin regulates receptor-operated Ca(2+) entry activity of TRPC6 in HEK-293 cells.
Cell Calcium32, 201-207, doi:10.
1016/s0143416002001550 (2002).