A longer isoform of Stim1 is a negative SOCE regulator but increases cAMP‐modulated NFAT signaling

Abstract

Alternative splicing is a potent modifier of protein function. Stromal interaction molecule 1 (Stim1) is the essential activator of store‐operated Ca2+ entry (SOCE) triggering activation of transcription factors. Here, we characterize Stim1A, a splice variant with an additional 31 amino acid domain inserted in frame within its cytosolic domain. Prominent expression of exon A is found in astrocytes, heart, kidney, and testes. Full‐length Stim1A functions as a dominant‐negative regulator of SOCE and ICRAC, facilitating sequence‐specific fast calcium‐dependent inactivation and destabilizing gating of Orai channels. Downregulation or absence of native Stim1A results in increased SOCE. Despite reducing SOCE, Stim1A leads to increased NFAT translocation. Differential proteomics revealed an interference of Stim1A with the cAMP‐SOCE crosstalk by altered modulation of phosphodiesterase 8 (PDE8), resulting in reduced cAMP degradation and increased PIP5K activity, facilitating NFAT activation. Our study uncovers a hitherto unknown mechanism regulating NFAT activation and indicates that cell‐type‐specific splicing of Stim1 is a potent means to regulate the NFAT signalosome and cAMP‐SOCE crosstalk.

A better brain? Alternative spliced STIM2 in hominoids arises with synapse formation and creates a gain-of-function variant

“…1B). In contrast to all previously analyzed variants (STIM2.1/STIM2ß, STIM1B, STIM1A [18], this splice event evolved more recently and the inserted unique protein domain can only be found in Catarrhini (old world monkeys): Theropithecus gelada (gelada baboons) and Hominoids (apes), implying a selective advantage that arose ~20 Million years ago (Fig. 1C).…”

Regulation of Store-Operated Ca2+Entry by IP3Receptors Independent of Their Ability to Release Ca2+

“…We suggest that the extent to which IP 3 Rs tune SOCE in different cells is probably determined by the strength of Gq signaling and endogenous interactions between STIM1 and Orai1. The latter is likely to depend on the relative expression of STIM1 and Orai1 (Woo et al ., 2020), the STIM isoforms expressed, expression of proteins that stabilize STIM1-Orai1 interactions (Darbellay et al ., 2011; Rana et al ., 2015; Rosado et al ., 2016; Knapp et al ., 2022), and the size and number of the MCS where STIM1 and Orai1 interact (Kang et al ., 2019). The multifarious contributors to SOCE suggest that cells may differ in whether they express “spare capacity”.…”

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

“…In skeletal muscle, the actin binding domain in STIM1L enables it to form permanent clusters with Orai1 thereby allowing for immediate activation of SOCE, which may be critical in excitable cells where there are large rapid changes in ER and cytosolic Ca 2+ levels facilitating faster and more efficient refilling of ER ( Darbellay et al, 2011 ). Database analysis predicts that several other STIM1 splice variants may occur and to date, two variants STIM1A and STIM1B have been characterized ( Knapp et al, 2021 ; Ramesh et al, 2021 ). STIM1A contains an additional A domain comprising 31 residues, adjacent to the ID domain ( Figure 1 ) and is highly conserved from fish to birds to mammals.…”

“…STIM1A was found in heart, kidney, astrocytes, and testes, but was not present in T-cells. STIM1 and STIM1A both co-localized with Orai1 after ER Ca 2+ depletion; surprisingly, however, STIM1A appears to function in a dominant negative manner, resulting in a decrease in SOCE possibly by interfering with the interaction between the STIM1 CAD/SOAR domain and Orai1 ( Knapp et al, 2021 ). STIM1B has a truncated C-terminus that includes a novel B domain downstream of the ID domain ( Ramesh et al, 2021 ).…”