Phasic characteristic of elementary Ca2+release sites underlies quantal responses to IP3

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Abstract
Ca2+ liberation by inositol 1,4,5‐trisphosphate (IP3) is ‘quantal’, in that low [IP3] causes only partial Ca2+ release, but further increasing [IP3] evokes more release. This characteristic allows cells to generate graded Ca2+ signals, but is unexpected, given the regenerative nature of Ca2+‐induced Ca2+ release through IP3 receptors. Two models have been proposed to resolve this paradox: (i) all‐or‐none Ca2+ release from heterogeneous stores that empty at varying [IP3]; and (ii) phasic liberation from homogeneously sensitive stores. To discriminate between these hypotheses, we imaged subcellular Ca2+ puffs evoked by IP3 in Xenopus oocytes where release sites were functionally uncoupled using EGTA. Puffs were little changed by 300 μM intracellular EGTA, but sites operated autonomously and did not propagate waves. Photoreleased IP3 generated flurries of puffs—different to the prolonged Ca2+ elevation following waves in control cells—and individual sites responded repeatedly to successive increments of [IP3]. These data support the second hypothesis while refuting the first, and suggest that local Ca2+ signals exhibit rapid adaptation, different to the slower inhibition following global Ca2+ waves.