Calcium transport and sensing in TRPC channels – New insights into a complex feedback regulation

Canonical TRP (TRPC) channels are a still enigmatic family of signaling molecules with multimodal sensing features. These channels enable Ca²⁺ influx through the plasma membrane to control a diverse range of cellular functions. Based on both regulatory- and recently uncovered structural features, TRPC channels are considered to coordinate Ca²⁺ and other divalent cations not only within the permeation path but also at additional sensory sites. Analysis of TRPC structures by cryo-EM identified multiple regulatory ion binding pockets. With this review, we aim at an overview and a critical discussion of the current concepts of divalent sensing by TRPC channels.