Extended synaptotagmin-1

Extended synaptotagmin-1 (E-Syt1) is a calcium-binding protein that mediates contact between the endoplasmic reticulum (ER) and the plasma membrane (UniProt: Q9BSJ8). It translocates to ER-plasma membrane appositions in response to elevated cytosolic calcium, where it tethers these membrane systems and facilitates their apposition. The protein also inhibits ADGRD1 G-protein-coupled receptor signaling under basal conditions and may participate in lipid transport via its barrel-like glycerophospholipid-binding domain.

E-Syt1 functions at critical junctures of cellular calcium signaling and membrane contact site biology, processes integral to neuronal physiology and synaptic function. UniProt records no primary disease associations for this protein.

In Alzheimer's disease, E-Syt1 is downregulated in post-mortem AD brain relative to age-matched controls (Chaparral AD proteomics), with a mean log2 fold-change of −0.44 across one subcellular fraction (TMT-labeled proteomics of four fractions: P2, P3, S2, S3). This reduction may reflect compromised ER-plasma membrane tethering and altered calcium homeostasis characteristic of AD pathology.