Sr 2+ has low efficiency in regulating spontaneous release at the Calyx of Held synapses

It has been known that Ca 2+ plays an essential role in mediating different modes of neurotransmitter release via different sensing mechanisms. Synaptotagmin 1, 2, and 9 were found to act as the Ca 2+ sensors for synchronous release and synaptotagmin 7 and Doc‐2 were proposed as the Ca 2+ sensors for asynchronous release. Comparatively, the Ca 2+ sensor for spontaneous release remains a mystery. At the Calyx of Held synapse, the Ca 2+ sensor for spontaneous release was found not identical to the sensor for synchronous release, synaptotagmin 2. As Ca 2+ sensors have different sensitivity to Sr 2+ and Ca 2+ and induce significantly different rate of vesicle release, Sr 2+ is traditionally used as a tool to examine the intrinsic properties of different Ca 2+ sensors. Here, we employed cell‐attached patch recording and presynaptic/postsynaptic whole‐cell recording at the Calyx of Held synapses of synaptotagmin 2 knock‐out mice to assay the Sr 2+ and Ca 2+ influx into the nerve terminal at resting potential and observed the effects of Ca 2+ and Sr 2+ on spontaneous neurotransmitter release. We found that the dwell time of single voltage gated Ca 2+ channel opening increased around threefold for Sr 2+ than Ca 2+ with the channel conductance unchanged; the divalent cation sensing machinery in regulating spontaneous release has much lower sensitivity to Sr 2+ than Ca 2+ . Thus, our study reveals some of the intrinsic properties of Ca 2+ sensor(s) of spontaneous transmitter release and provided an insight into the underlying mechanisms.