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Syntaxin (Syn)-1A mediates exocytosis of predocked insulin-containing secretory granules (SGs) during first-phase glucose-stimulated insulin secretion (GSIS) in part via its interaction with plasma membrane (PM)-bound L-type voltage-gated calcium channels (Ca v ). In contrast, Syn-3 mediates exocytosis of newcomer SGs that accounts for second-phase GSIS. We now hypothesize that the newcomer SG Syn-3 preferentially binds and modulates R-type Ca v  opening, which was postulated to mediate second-phase GSIS. Indeed, glucose-stimulation of pancreatic islet β-cell line INS-1 induced a predominant increase in interaction between Syn-3 and Ca v α1 pore-forming subunits of R-type Ca v 2.3 and to lesser extent L-type Ca v s, while confirming the preferential interactions between Syn-1A with L-type (Ca v 1.2, Ca v 1.3) Ca v s. Consistently, direct binding studies employing heterologous HEK cells confirmed that Syn-3 preferentially binds Ca v 2.3, whereas Syn-1A prefers L-type Ca v s. We then used siRNA knockdown (KD) of Syn-3 in INS-1 to study the endogenous modulatory actions of Syn-3 on Ca v  channels. Syn-3 KD enhanced Ca 2+  currents by 46% attributed mostly to R- and L-type Ca v s. Interestingly, while the transmembrane domain of Syn-1A is the putative functional domain modulating Ca v  activity, it is the cytoplasmic domain of Syn-3 that appears to modulate Ca v  activity. We conclude that Syn-3 may mimic Syn-1A in the ability to bind and modulate Ca v s, but preferring Ca v 2.3 to perhaps participate in triggering fusion of newcomer insulin SGs during second-phase GSIS.

Syntaxin-3 Binds and Regulates Both R- and L-Type Calcium Channels in Insulin-Secreting INS-1 832/13 Cells