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 Ca^2+- dependent cellular functions in vivo, and can explain the normal function of most physiological systems in DD patients.