1.A.4.1.7
Short transient receptor channel 5 (TrpC5 or Htrp5) (transports Ca²⁺ and Sr²⁺ in the presence of Orai1 and STIM1 (TC# 1.A.52.1.1) (Ma et al., 2008). It is a cold-transducer in the peripheral nervous system (Zimmermann et al., 2011). A small-molecule inhibitor suppresses progressive kidney disease in rats (Zhou et al. 2017).  ORAI and TRP, and the transmembrane Ca²⁺ sensors, stromal interaction molecules (STIMs), are involved in thrombosis and thrombo-inflammation in platelets and immune cells. Disregulated store-operated Ca²⁺ (SOCE) fluxes in platelets and immune cells are responsible, and the potential of SOCE inhibition as a therapeutic option to prevent or treat arterial thrombosis as well as thrombo-inflammatory disease states such as ischemic stroke have been considered (Mammadova-Bach et al. 2019). The molecular architecture of the Galpha(i)-bound TRPC5 ion channel has been solved (Won et al. 2023). G-protein coupled receptors (GPCRs) and ion channels serve as key molecular switches through which extracellular stimuli are transformed into intracellular effects, and it has long been postulated that ion channels are direct effector molecules of the alpha subunit of G-proteins (Galpha; see TC family 8.A.43). Won et al. 2023 presented cryo-EM structures of the human TRPC5-Galpha(i3) complexes with a 4:4 stoichiometry in lipid nanodiscs. Galpha(i3) binds to the ankyrin repeat edge of TRPC5 ~ 50 Å away from the cell membrane. Electrophysiological analyses showed that Galpha(i3) increases the sensitivity of TRPC5 to phosphatidylinositol 4,5-bisphosphate (PIP(2)), thereby rendering TRPC5 more easily opened in the cell membrane, where the concentration of PIP(2) is physiologically regulated. These observations show that ion channels are one of the direct effector molecules of Galpha proteins triggered by GPCR activation-providing a structural framework for unraveling the crosstalk between two major classes of transmembrane proteins: GPCRs and ion channels (Won et al. 2023).