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

Abstract

Shin contributed equally to this workDarier's disease (DD) is a high penetrance, autosomal dominant mutation in the ATP2A2 gene, which encodes the SERCA2 Ca 2+ pump. Here we have used a mouse model of DD, a SERCA2 +/± mouse, to de®ne the adaptation of Ca 2+ signaling and Ca 2+ -dependent exocytosis to a deletion of one copy of the SERCA2 gene. The [Ca 2+ ] i transient evoked by maximal agonist stimulation was shorter in cells from SERCA2 +/± mice, due to an up-regulation of speci®c plasma membrane Ca 2+ pump isoforms. The change in cellular Ca 2+ handling caused~50% reduction in [Ca 2+ ] 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 Ca 2+ sensors for exocytosis synaptotagmins I and III in cells from SERCA2 +/± mice. Accordingly, exocytosis was~10-fold more sensitive to Ca 2+ in cells from SERCA2 +/± mice. These ®ndings reveal a remarkable plasticity and adaptability of Ca 2+ signaling and Ca 2+ -dependent cellular functions in vivo, and can explain the normal function of most physiological systems in DD patients.

Darier’s disease: a calcium-signaling perspective

“…In yet another interesting study, the same group working on a murine model of the disease (SERCA+/-heterozygous mice) demonstrated the effect of defective SERCA pumps on exocytosis. Secretion of amylase was about ten-fold more sensitive to Ca 2+ in SERCA2+/-mice compared to the wild type [31]. More recently in 2006, Hiroshi Suzuki and colleagues reported a comprehensive analysis of 51 SERCA mutants associated with DD.…”

Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca2+ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease

“…However, of the multiple isoforms of SERCA1, -2, or -3, only SERCA2b is expressed in keratinocytes (Lytton and MacLennan, 1988;Ruiz-Perez et al, 1999). The mutated SERCA2 fails to sequester cytosolic Ca 2ϩ into the endoplasmic reticulum (ER) lumen, thereby disturbing the otherwise normal Ca 2ϩ homeostasis circuitry within the cells (Zhao et al, 2001;Ahn et al, 2003). Although oral retinoids, such as isotretinoin, have been shown to reduce hyperkeratosis (Burge and Wilkinson, 1992), the mechanism behind dysfunction of SERCA2 resulting in keratosis remains elusive.…”

Latrophilin‐2 is a novel component of the epithelial‐mesenchymal transition within the atrioventricular canal of the embryonic chicken heart

“…Latrophilin-2 may also be involved in calcium signaling within the cell but as latrotoxin does not bind latrophilin-2, direct examination of changes in calcium flux by lactophilin-2 cannot be as easily observed. Our microarray results suggest that loss of latrophilin-2 message likely produces up-regulation of SERCA2, a transporter that functions to remove calcium from the cytosol and down-regulation of its inhibitor, phospholamban (Zhao et al, 2001). There was also down-regulation of the alpha1C subunit of L-type calcium channels observed.…”