STIM1 participates in the contractile rhythmicity of HL-1 cells by moderating T-type Ca2+ channel activity

Abstract

STIM1 plays a crucial role in Ca(2+) homeostasis, particularly in replenishing the intracellular Ca(2+) store following its depletion. In cardiomyocytes, the Ca(2+) content of the sarcoplasmic reticulum must be tightly controlled to sustain contractile activity. The presence of STIM1 in cardiomyocytes suggests that it may play a role in regulating the contraction of cardiomyocytes. The aim of the present study was to determine how STIM1 participates in the regulation of cardiac contractility. Atomic force microscopy revealed that knocking down STIM1 disrupts the contractility of cardiomyocyte-derived HL-1 cells. Ca(2+) imaging also revealed that knocking down STIM1 causes irregular spontaneous Ca(2+) oscillations in HL-1 cells. Action potential recordings further showed that knocking down STIM1 induces early and delayed afterdepolarizations. Knocking down STIM1 increased the peak amplitude and current density of T-type voltage-dependent Ca(2+) channels (T-VDCC) and shifted the activation curve toward more negative membrane potentials in HL-1 cells. Biotinylation assays revealed that knocking down STIM1 increased T-VDCC surface expression and co-immunoprecipitation assays suggested that STIM1 directly regulates T-VDCC activity. Thus, STIM1 is a negative regulator of T-VDCC activity and maintains a constant cardiac rhythm by preventing a Ca(2+) overload that elicits arrhythmogenic events.

Ca2+/calmodulin-activated phosphodiesterase 1A is highly expressed in rabbit cardiac sinoatrial nodal cells and regulates pacemaker function

“…Properties of I f current in HL-1 cells are similar to those in SANC; inhibition of I f current in HL-1 cells as in SANC significantly suppresses diastolic depolarization and reduces automaticity. L-type and T-type Ca channels, inward rectifier K + channels, and Stim1 are also expressed in HL-1 cells [25–28]. The effects of application of thapsigargin and ryanodine to HL-1 cells as well as effects of PKA activation are the same as in SANC.…”

AMPA Receptors Are Involved in Store-Operated Calcium Entry and Interact with STIM Proteins in Rat Primary Cortical Neurons

“…However, previous studies also demonstrated the presence of SOCE in cultured neurons (Emptage et al, 2001; Kachoei et al, 2006; Berna-Erro et al, 2009; Klejman et al, 2009; Gruszczynska-Biegala et al, 2011). Additionally, the SOCE component STIM1 does not only activate Orai1, but it also modulates the activity of Ca V 1.2 (Park et al, 2010; Harraz and Altier, 2014) and Ca V 3.1 (Nguyen et al, 2013) VGCCs, the plasma membrane Ca 2+ adenosine triphosphatase pump (Krapivinsky et al, 2011), and metabotropic glutamate one receptor-dependent TRPC3 (Hartmann et al, 2014). The results demonstrate that STIM proteins may impact various Ca 2+ -related pathways in neurons (Harraz and Altier, 2014; Kraft, 2015; Majewski and Kuznicki, 2015; Moccia et al, 2015).…”

“…STIM2 was previously shown to promote the PKA-dependent surface delivery of GluA1 (Garcia-Alvarez et al, 2015). STIM1 prevents the surface expression of Ca V 1.2 (Park et al, 2010) and Ca V 3.1 (Nguyen et al, 2013), but it is unknown whether STIM1 also augments the surface expression of AMPARs.…”

“…Recent studies found that STIM1, in addition to Orai activation, inhibits Ca 2+ entry that is mediated by T- and L-type channels in excitable cells (Park et al, 2010; Nguyen et al, 2013). Other studies reported that STIM2 is involved in the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)-dependent phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 by coupling PKA to the AMPA receptors (AMPARs) in a SOCE-independent manner (Garcia-Alvarez et al, 2015).…”

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

“…In addition, Nguyen et al (73) have shown that in HL 1 cells, a reduction in STIM1 expression was sufficient to disrupt contraction, induce Ca 2ϩ oscillations and associated arrhythmias as well as increased TTCC activity and expression. Taken together, these studies provide strong support for a key role for STIM1/Orai1-mediated SOCE in regulating cardiomyocyte Ca 2ϩ homeostasis.…”