Transient Receptor Potential (TRP) Channels and Calcium Signaling: A Structural Point of View

Transient receptor potential (TRP) cation channels play diverse roles in cellular Ca²⁺ signaling. First, as Ca²⁺-permeable channels that respond to a variety of stimuli, TRP channels can directly initiate cellular Ca²⁺ signals. Second, as nonselective cation channels, TRP channel activation leads to membrane depolarization, influencing Ca²⁺ influx via voltage-gated and store-operated Ca²⁺ channels. Finally, Ca²⁺ modulates the activity of most TRP channels, allowing them to function as molecular effectors downstream from intracellular Ca²⁺ signals. The past decade has seen a transformation of the TRP field. Once lacking high-resolution structures, we now have cryogenic electron microscopy (cryo-EM) structures across all seven TRP subfamilies, including multiple ligand-bound, lipid-bound, Ca²⁺-bound, and disease-mutant states. The rapid expansion of cryo-EM structures across all TRP subfamilies has transformed our understanding of Ca²⁺ permeation, selectivity, and Ca²⁺-dependent gating. These structures, together with functional and computational approaches, reveal how TRP channels coordinate Ca²⁺, how Ca²⁺ binding modulates pore opening or inactivation, and why some TRPs are highly Ca²⁺ selective while others are Ca²⁺ impermeable. This structural framework now underpins efforts to develop targeted therapies for a wide range of TRP-related diseases.