ANO8 (anoctamin 8) is an intracellular member of the anoctamin protein family that serves as a key membrane tether at endoplasmic reticulum-plasma membrane (ER/PM) junctions rather than functioning as a conventional calcium-activated chloride channel 1. Unlike plasma membrane anoctamins, ANO8 shows poor membrane expression and is mostly retained in the cytosol, though it can produce transient Ca2+-activated Cl- currents when overexpressed 2. ANO8's primary function involves tethering the ER and PM to form specialized contact sites essential for calcium signaling 3. At these junctions, ANO8 facilitates STIM1-STIM1 and STIM1-Orai1 interactions, assembling core Ca2+ signaling proteins including Orai1, PMCA, STIM1, IP3 receptors, and SERCA2 3. This organization enables a novel form of Orai1 channel inactivation by enhancing SERCA2-mediated calcium influx into the ER, controlling the efficiency of receptor-stimulated Ca2+ signaling and preventing Ca2+ toxicity 3. Clinically, ANO8 has been implicated in several diseases: rare variants confer high risk for ADHD 4, mutations are associated with intrahepatic cholestasis of pregnancy 5, and altered expression correlates with atrial fibrillation rhythm control 6.