8.A.78 The Insulin Secretion-regulating Lipid Transporter TMEM24 (TMEM24) Family 

Insulin is secreted by pancreatic β cells in response to glucose stimulation. Its release is controlled by the interplay of calcium and phosphoinositide signaling pathways. A rapid release phase, in which insulin containing granules that are already docked and primed at the plasma membrane (PM) undergo exocytosis, is followed by slow release. In this second phase, granules are docked and primed and then released in a series of bursts, each triggered by a spike in cytosolic Ca²⁺. 

TMEM24 is an endoplasmic reticulum (ER) protein that concentrates at ER-PM contact sites, where it tethers the two bilayers (Lees et al. 2017). TMEM24 binding “in trans” to the PM is negatively regulated by phosphorylation in response to elevation of cytosolic Ca²⁺, so that TMEM24 transiently dissociates from the PM as Ca²⁺ concentration spikes and then reassociates with this membrane upon dephosphorylation. TMEM24 contains a lipid transport module of the synaptotagmin-like, mitochondrial and lipid-binding protein (SMP) family (TC# 9.A.57), which binds glycerolipids with a preference for phosphatidylinositol (PI). Thus, TMEM24 helps deliver PI, which is synthesized in the ER, to the PM, where it is converted to phosphatidylinositol-4,5-bisphosphate [PI(4,5)P₂] to replenish pools of this lipid hydrolyzed during glucose-stimulated signaling. Supporting a key role of TMEM24 in the coordination of Ca²⁺ and phosphoinositide signaling, the lipid transport function of TMEM24 is essential for sustaining the intracellular Ca²⁺ oscillations that trigger bursts of insulin granule release and hence insulin secretion. PI(4,5)P₂ is required for Ca²⁺-dependent exocytosis. It also controls the activity of PM ion channels that regulate cytosolic Ca²⁺ levels and is the precursor of IP₃, which also helps to modulate cytosolic Ca²⁺ by triggering Ca²⁺ release from the ER. Thus, in insulin-secreting cells, TMEM24 participates in coordinating Ca²⁺ and phosphoinositide signaling pathways to cause pulsatile insulin secretion (Lees et al. 2017).

These findings implicate ER-PM contact sites and TMEM24 in the direct regulation of PM phosphoinositide pools, offering insight into the mechanisms of cellular phosphoinositide dynamics. More specifically, they elaborate the mechanisms underlying insulin secretion, which is impaired in patients with type II diabetes.