TRPC4 Membrane Protein Introduction

Introduction of TRPC4

Short transient receptor potential channel 4 (TRPC4), also known as Trp-related protein 4, is encoded by the TRPC4 gene. TRPC4 belongs to the canonical subfamily of transient receptor potential cation channels. Mutation in this gene may be involved in generalized epilepsy with photosensitivity. TRPC4 contains 6 transmembrane regions, a pore region, a caveolin-binding domain and a PDZ domain binding region at the C terminus. TRPC4 is widely expressed in heart, pancreas, placenta, brain, and kidney, especially in the cortico-limbic regions of the brain with high abundance. In addition, TRPC4 is also present in midbrain dopaminergic neurons in the ventral tegmental area and the substantia nigra.

Function of TRPC4 Membrane Protein

TRPC4 can form a nonspecific calcium-permeable cation channel that may play a role in many biological processes including vasodilation, endothelial permeability, gamma-aminobutyric acid secretion, oligodendrocyte differentiation, regulation of cytosolic calcium ion concentration, cell proliferation and neurotransmitter release. It is possibly controlled by a phosphatidylinositol second messenger system activated by Gαi-coupled receptors, Gαq-coupled receptors and tyrosine kinases. For another, it may also be activated by depletion of intracellular calcium. As an ion channel, it has an enhanced permeability to barium over calcium, and its translocation to the plasma membrane is associated with the interaction with spectrin. There is no experiment structure available for human TRPC4, but we can take a zebrafish TRPC4 structure (PDB: 6G1K) from the reference (Fig.1).

Fig.1 Electron cryo-microscopy structure of the canonical TRPC4 ion channel. (Vinayagam, 2018)

Application of TRPC4 Membrane Protein in Literature

1. Cheung S.Y., et al. TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A. Oncotarget. 2018, 9(51):29634-29643. PubMed ID: 30038709
   
   

   This article confirms the existence of harmful reaction to Englerin A in mice, suggesting that it depends on a combination of TRPC4 and TRPC5 which therefore overlaps partially with TRPC4-dependent cancer cell cytotoxicity.

2. Alom F., et al. Possible antagonistic effects of the TRPC4 channel blocker ML204 on M2 and M3 muscarinic receptors in mouse ileal and detrusor smooth muscles and atrial myocardium. J Vet Med Sci. 2018, 80(9):1407-1415. PubMed ID: 29973432
   
   

   This article suggests that ML204, a potent TRPC4 channel blocker, might exhibit antagonistic actions on M₂ and M₃ muscarinic receptors. Additionally, the inhibitory effects of ML204 against electrical field stimulation-induced cholinergic contractions might be ascribed to this receptor antagonism rather than the suppression of TRPC4 channel activity.

3. Griffin C.S., et al. Muscarinic receptor-induced contractions of the detrusor are impaired in TRPC4 deficient mice. Sci Rep. 2018, 8(1):9264. PubMed ID: 29915209
   
   

   This article demonstrates that TRPC4 channels are associated with cholinergic-mediated and spontaneous contractions of the murine detrusor. Additionally, expression of TRPC5 is up-regulated in TRPC4^-/- detrusor strips, suggesting TRPC5 may to some extent compensate for the lack of TRPC4 channels.

4. Vinayagam D., et al. Electron cryo-microscopy structure of the canonical TRPC4 ion channel. Elife. 2018, 7. pii: e36615. PubMed ID: 29717981
   
   

   This article reports the electron cryo-microscopy structure of zebrafish TRPC4 in its apo, closed state at an overall resolution of 3.6 Å.

5. Zhang B., et al. TRPC6 and TRPC4 Heteromultimerization Mediates Store Depletion-Activated NCX1 Reversal in Proliferative Vascular Smooth Muscle Cells. Channels (Austin). 2018, 12(1):119-125. PubMed ID: 29560783
   
   

   This article demonstrates that TRPC4-TRPC6 hetero-multimerization linked depletion of Ca2+ store and STIM1 accumulation with Na+/Ca2+ exchange reversal in proliferative vascular smooth muscle cells.

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Reference

1. Vinayagam D, et al. (2018). Electron cryo-microscopy structure of the canonical TRPC4 ion channel. Elife, pii: e36615.

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