Subunit composition, molecular environment, and activation of native TRPC channels encoded by their interactomes

Inhibition of Canonical Transient Receptor Potential Channels 4/5 with Highly Selective and Potent Small-Molecule HC-070 Alleviates Mechanical Hypersensitivity in Rat Models of Visceral and Neuropathic Pain

“…It was soon found that homomeric TRPC4 and TRPC5 can form functional channels, in contrast to TRPC1 [ 37 ]. A recent study established that central TRPC1/C4/C5 channels co-assemble into a functional heterotetrameric channel and macromolecular complexes consisting of several other proteins in the brain [ 38 ]. This finding suggests that small-molecule inhibitors of TRPC4 and TRPC5 channels crossing the blood–brain barrier (BBB) are likely to block heterotetrameric complexes and do not show selectivity over TRPC4 or TRPC5 subtypes in vivo.…”

TR(i)P Goes On: Auxiliary TRP Channel Subunits?

“…19 Subsequent functional studies in native hippocampal neurons and 2 heterologous expression systems, HEK 293 cells and Xenopus laevis oocytes, showed that TRPC-mGluR1 complexes generate robust cation currents that are effectively activated by intracellular Ca 2+ delivered via the PLC pathway (Figure [B]). 19 After channel activation, increased intracellular Ca 2+ triggers (complete) channel closure, presumably through Ca 2+dependent binding of calmodulin to a carboxy-terminal binding domain, as recently suggested by 3-dimensional structures of TRPC4. 34 As guanine nucleotide-binding protein-coupled receptors, the mGluR1 proteins outnumber the TRPC1, TRPC4, and TRPC5 proteins in the brain.…”

“…This is partly due to low expression levels. For example, the overall abundance of TRPC proteins in the rodent brain is rather low, 19 more than 500-fold lower than that of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate) receptors, 20 GABA (metabotropic gamma-aminobutyric acid) type B receptors, 21 or plasma membrane Ca 2+ pumps. 22 Nevertheless, TRPC channels are critical for a wide range of processes in the mammalian brain, from neuronal growth and synaptogenesis to transmitter release, synaptic transmission, and plasticity.…”

“…CaM, calmodulin; ER, endoplasmic reticulum; Glu, glutamate; IP3, inositol 1,4,5-trisphosphate; MS, mass spectrometry; PLC β, phospholipase β; and PM, plasma membrane. Adapted from Kollewe et al 19 with permission. Copyright ©2022.…”

“…The experimental approach involved the use of multiple antibodies (a total of 24 antibodies against TRPC proteins were used), each recognizing independent epitopes on the respective TRPC protein, unbiased and quantitative analysis of all proteins in the affinity purification eluates, sensitivity and dynamic range of MS analysis over a linear range of up to 4 orders of magnitude, stringent negative controls provided by single and multiple TRP gene-deficient (knockout) tissues, and the application of consistency criteria that reduced the influence of misallocations due to peculiarities in the binding properties of individual antibodies. 19…”