Plasticity and adaptation of Ca2+ signaling and Ca2+-dependent exocytosis in SERCA2+/− mice

Darier's disease (DD) is a high penetrance, autosomal dominant mutation in the ATP2A2 gene, which encodes the SERCA2 Ca2+ pump. Here we have used a mouse model of DD, a SERCA2+/− mouse, to define the adaptation of Ca2+ signaling and Ca2+‐dependent exocytosis to a deletion of one copy of the SERCA2 gene. The [Ca2+]i transient evoked by maximal agonist stimulation was shorter in cells from SERCA2+/− mice, due to an up‐regulation of specific plasma membrane Ca2+ pump isoforms. The change in cellular Ca2+ handling caused ∼50% reduction in [Ca2+]i oscillation frequency. Nonetheless, agonist‐stimulated exocytosis was identical in cells from wild‐type and SERCA2+/− mice. This was due to adaptation in the levels of the Ca2+ sensors for exocytosis synaptotagmins I and III in cells from SERCA2+/− mice. Accordingly, exocytosis was ∼10‐fold more sensitive to Ca2+ in cells from SERCA2+/− mice. These findings reveal a remarkable plasticity and adaptability of Ca2+ signaling and Ca2+‐dependent cellular functions in vivo, and can explain the normal function of most physiological systems in DD patients.