The closing and opening of TRPC channels by Homer1 and STIM1

Influx of Ca ²⁺ is a central component of the receptor-evoked Ca ²⁺ signal. A ubiquitous form of Ca ²⁺ influx comes from Ca ²⁺ channels that are activated in response to depletion of the endoplasmic reticulum Ca ²⁺ stores and are thus named the store-operated Ca ²⁺-influx channels (SOCs). One form of SOC is the transient receptor potential canonical (TRPC) channels. A major question in the field of Ca ²⁺ signalling is the molecular mechanism that regulates the opening and closing of these channels. All TRPC channels have a Homer-binding ligand and two conserved negative charges that interact with two terminal lysines of the stromal interacting molecule 1 (STIM1). The Homer and STIM1 sites are separated by only four amino acid residues. Based on available results, we propose a molecular mechanism by which Homer couples TRPC channels to IP ₃ receptors (IP ₃Rs) to keep these channels in the closed state. Dissociation of the TRPCs-Homer-IP ₃Rs complex allows STIM1 access to the TRPC channels negative charges to gate open these channels.