STIM1-Orai1–mediated Ca²⁺ entry is particularly important for platelet agonists acting via the ITAM motif and PLCγ2. All stimulatory platelet agonists elevate cytosolic Ca²⁺ as part of their activation mechanism. Two major routes exists: one utilizing the ITAM motif present on the FcRγ chain leading to activation of PLCγ2, the other utilized by G-protein–linked receptors activating PLCβ. Both produce inositol-1,4,5-trisphophate (IP₃), which releases Ca²⁺ from intracellular stores via the IP₃Rs. Store depletion causes Ca²⁺ to come off STIM1, allowing STIM1 to oligomerize and activate Orai1. Ca²⁺ entry via this pathway is particularly important for platelet activation during thrombus formation in vivo where ITAM engagement is necessary. For platelet activation via G-protein–linked receptors, the more rapid Ca²⁺ release from stores (and additionally Ca²⁺ entry from Orai1 and non-Orai1 channels such as TRPC6) may synergize with other messengers (such as PKC and PI-3K) to effect cell activation. Professional illustration by Kenneth X. Probst.