Fig. 7. Model for TMEM24 modulation of pulsatile insulin secretion through effects on phosphoinositide and calcium dynamics.

(Top left) In insulin-secreting cells at resting state, ER-anchored TMEM24 localizes to ER-PM contact sites via interaction between its basic C-terminal region and the PM. In this state, TMEM24 transfers PI from the ER to the PM, maintaining the pool of PM phosphoinositides, including PI(4)P and PI(4,5)P₂. PI(4,5)P₂ interacts with voltage-gated calcium channels, increasing their responsiveness to depolarization caused by glucose stimulation. PI(4,5)P₂ also participates in priming of insulin secretory granules in preparation for exocytosis. (Right) Upon glucose stimulation or membrane depolarization, calcium influx through the calcium channels stimulates insulin release while activating the PKC pathway, causing phosphorylation of the TMEM24 C terminus. This C-terminal modification is responsible for the dispersion of TMEM24 from ER-PM contacts into the reticular ER. Transfer of PI to the PM by TMEM24 is abolished. Calcium also activates PLCδ, which is responsible for cleavage of PI(4,5)P₂ to form DAG and IP₃, partially depleting PI(4,5)P₂ from the PM and further elevating levels of cytosolic calcium via activation of IP₃ receptors in the ER membrane. The loss of PI(4,5)P₂ eventually promotes the closed state of PM calcium channels and terminates IP₃ production. (Bottom left) Calcium-induced activation of the S/T-phosphatase calcineurin/PP2B results in dephosphorylation of the TMEM24 C terminus, allowing TMEM24 to repopulate ER-PM contact sites. PI transfer to the PM resumes to replenish PI(4)P and PI(4,5)P₂ pools, reenabling calcium channel opening and priming a new population of insulin granules. The oscillatory interplay between calcium and TMEM24 continues in a cyclical fashion for the duration of glucose stimulation.