Illustration of the proposed mechanisms for facilitation. Voltage-gated Ca2+ channels(VGCCs) open during the first action potential (AP) and allow Ca2+ influx (ICa). During the first action potential, Ca2+ influx fails to fully activate Syt1 and trigger fusion.
A) The residual Ca2+ hypothesis: Cares from the first AP adds to Calocal during the second AP. Because the fusion sensor binds Ca2+ in a supralinear manner, a small increase in the Ca2+ signal drives a large increase in p.
(B) Residual Ca2+ binds to a facilitation sensor: a high-affinity sensor, distinct from Syt1, binds to Cares in between APs and raises p by interacting with the fusion machinery.
(C) Spike broadening: inactivation of K+ channels during the first AP broadens the waveform of the second AP, prolonging the time course and total amount of ICa.
(D) Calcium current facilitation: Ca2+ from the first AP binds to NCS-1 or CaM, which interact with the IQ-like motif (IM) on the intracellular C terminus of P/Q channels to increase ICa during the second AP.
(E) Buffer saturation: during the first AP, there is enough unbound Ca2+ buffer to capture incoming ions and decrease the Ca2+ signal sensed by Syt1 (Calocal). During the second AP, the buffer becomes saturated and cannot constrain Calocal.
