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Neuron. 2017 Feb 22;93(4):867-881.e6. doi: 10.1016/j.neuron.2017.01.010. Epub 2017 Feb 2.

Axonal Endoplasmic Reticulum Ca2+ Content Controls Release Probability in CNS Nerve Terminals.

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Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
Department of Physics, University of Oxford, Oxford, OX1 3NP, UK.
Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:


Although the endoplasmic reticulum (ER) extends throughout axons and axonal ER dysfunction is implicated in numerous neurological diseases, its role at nerve terminals is poorly understood. We developed novel genetically encoded ER-targeted low-affinity Ca2+ indicators optimized for examining axonal ER Ca2+. Our experiments revealed that presynaptic function is tightly controlled by ER Ca2+ content. We found that neuronal activity drives net Ca2+ uptake into presynaptic ER although this activity does not contribute significantly to shaping cytosolic Ca2+ except during prolonged repetitive firing. In contrast, we found that axonal ER acts as an actuator of plasma membrane (PM) function: [Ca2+]ER controls STIM1 activation in presynaptic terminals, which results in the local modulation of presynaptic function, impacting activity-driven Ca2+ entry and release probability. These experiments reveal a critical role of presynaptic ER in the control of neurotransmitter release and will help frame future investigations into the molecular basis of ER-driven neuronal disease states.


Ca(2+) imaging; ER-GCaMP; GCaMP6; STIM1; low affinity Ca(2+) indicator; presynaptic endoplasmic reticulum

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