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

In the mammalian brain TRPC channels, a family of Ca²⁺-permeable cation channels, are involved in a variety of processes from neuronal growth and synapse formation to transmitter release, synaptic transmission and plasticity. The molecular appearance and operation of native TRPC channels, however, remained poorly understood. Here, we used high-resolution proteomics to show that TRPC channels in the rodent brain are macro-molecular complexes of more than 1 MDa in size that result from the co-assembly of the tetrameric channel core with an ensemble of interacting proteins (interactome). The core(s) of TRPC1-, C4-, and C5-containing channels are mostly heteromers with defined stoichiometries for each subtype, whereas TRPC3, C6, and C7 preferentially form homomers. In addition, TRPC1/C4/C5 channels may co-assemble with the metabotropic glutamate receptor mGluR1, thus guaranteeing both specificity and reliability of channel activation via the phospholipase-Ca²⁺ pathway. Our results unveil the subunit composition of native TRPC channels and resolve the molecular details underlying their activation.

Kollewe A, Schwarz Y, Oleinikov K, Raza A, Haupt A, Wartenberg P, Wyatt A, Boehm U, Ectors F, Bildl W, Zolles G, Schulte U, Bruns D, Flockerzi V, Fakler B. Subunit composition, molecular environment, and activation of native TRPC channels encoded by their interactomes. Neuron. 2022 Oct 10:S0896-6273(22)00868-6. doi: 10.1016/j.neuron.2022.09.029. Epub ahead of print.

PMID: 36257322

DOI: 10.1016/j.neuron.2022.09.029