Intracellular calcium dependence of large dense-core vesicle exocytosis inthe absence of synaptotagmin I

Synaptotagmin I is a synaptic vesicle-associated protein essential for sync hronous neurotransmission. We investigated its impact on the intracellular Ca2+-dependence of large dense-core vesicle (LDCV) exocytosis by combining Ca2+-uncaging and membrane capacitance measurements in adrenal slices from mouse synapto-tagmin I null mutants. Synaptotagmin I-deficient chromaffin c ells displayed prolonged exocytic delays and slow, yet Ca2+-dependent fusio n rates, resulting in strongly reduced LDCV release in response to short de polarizations. Vesicle recruitment, the shape of individual amperometric ev ents, and endocytosis appeared unaffected. These findings demonstrate that synaptotagmin I is required for rapid, highly Ca2+-sensitive LDCV exocytosi s and indicate that it regulates the equilibrium between a slowly releasabl e and a readily releasable state of the fusion machinery. Alternatively, sy naptotagmin I could function as calcium sensor for the readily releasable p ool, leading to the destabilization of the pool in its absence.