Two possible mechanisms. (A) Cartoon of STIM–ORAI interaction at an ER–plasma membrane junction. The ORAI1 channel itself is highlighted in red as the target of SMase D, representing a possible mechanism in which SMase D acts on sphingomyelin tightly bound to the channel. This mechanism would parallel the action of SMase D on K⁺ channels. (B) In an alternative—or additional—mechanism, SMase D might suppress channel function by altering the lipid microdomain surrounding the channel. The relevant changes could be in a relatively localized lipid microdomain, as portrayed with the red highlight, or could involve the plasma membrane of the entire ER–plasma membrane junction.