Sr2+ triggers neurotransmitter release similar to Ca2+, but less efficiently. We now show that in synaptotagmin 1 knockout mice, the fast component of both Ca2+- and Sr2+-induced release is selectively impaired, suggesting that both cations partly act by binding to synaptotagmin 1. Both the C2A and the C2B domain of synaptotagmin 1 bind Ca2+ in phospholipid complexes, but only the C2B domain forms Sr2+/phospholipid complexes; therefore, Sr2+ binding to the C2B domain is sufficient to trigger fast release, although with decreased efficacy. Ca2+ induces binding of the synaptotagmin C2 domains to SNARE proteins, whereas Sr2+ even at high concentrations does not. Thus, triggering of the fast component of release by Sr2+ as a Ca2+ agonist involves the formation of synaptotagmin/phospholipid complexes, but does not require stimulated SNARE binding.
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