Sr²⁺ binding to the Ca²⁺ binding site of the synaptotagmin 1 C₂B domain triggers fast exocytosis without stimulating SNARE interactions

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.