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Ryanodine receptor (RyR)\u2010sensitive stores in hypothalamic neurohypophysial system (HNS) terminals produce sparks of intracellular calcium ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) that are voltage\u2010dependent. We hypothesised that voltage\u2010elicited increases in intraterminal calcium are crucial for neuropeptide secretion from presynaptic terminals, whether from influx through voltage\u2010gated calcium channels and\/or from such voltage\u2010sensitive ryanodine\u2010mediated calcium stores. Increases in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>upon depolarisation in the presence of voltage\u2010gated calcium channel blockers, or in the absence of [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>o<\/jats:sub>, still give rise to neuropeptide secretion from HNS terminals. Even in 0 [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>o<\/jats:sub>, there was nonetheless an increase in capacitance suggesting exocytosis upon depolarisation. This was blocked by antagonist concentrations of ryanodine, as was peptide secretion elicited by high K<jats:sup>+<\/jats:sup>in 0 [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>o<\/jats:sub>. Furthermore, such depolarisations lead to increases in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>. Pre\u2010incubation with BAPTA\u2010AM resulted in &gt;\u00a050% inhibition of peptide secretion elicited by high K<jats:sup>+<\/jats:sup>in 0 [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>o<\/jats:sub>. Nifedipine but not nicardipine inhibited both the high K<jats:sup>+<\/jats:sup>response for neuropeptide secretion and intraterminal calcium, suggesting the involvement of CaV1.1 type channels as sensors in voltage\u2010induced calcium release. Importantly, RyR antagonists also modulate neuropeptide release under normal physiological conditions. In conclusion, our results indicate that depolarisation\u2010induced neuropeptide secretion is present in the absence of external calcium, and calcium release from ryanodine\u2010sensitive internal stores is a significant physiological contributor to neuropeptide secretion from HNS terminals.<\/jats:p>","DOI":"10.1111\/jne.12840","type":"journal-article","created":{"date-parts":[[2020,2,25]],"date-time":"2020-02-25T21:21:48Z","timestamp":1582665708000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Voltage\u2010induced Ca<sup>2+<\/sup>release by ryanodine receptors causes neuropeptide secretion from nerve terminals"],"prefix":"10.1111","volume":"32","author":[{"given":"Cristina","family":"Vel\u00e1zquez\u2010Marrero","sequence":"first","affiliation":[{"name":"Institute of Neurobiology University of Puerto Rico San Juan PR USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward 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