Role of Orai‐family channels in the activation and regulation of transcriptional activity

Abstract

Store operated Ca2+ entry (SOCE) is a cornerstone for the maintenance of intracellular Ca2+ homeostasis and the regulation of a variety of cellular functions. SOCE is mediated by STIM and Orai proteins following the activation of inositol 1,4,5‐trisphosphate receptors. Then, a reduction of the endoplasmic reticulum intraluminal Ca2+ concentration is sensed by STIM proteins, which undergo a conformational change and activate plasma membrane Ca2+ channels comprised by Orai proteins. STIM1/Orai‐mediated Ca2+ signals are finely regulated and modulate the activity of different transcription factors, including certain isoforms of the nuclear factor of activated T‐cells, the cAMP‐response element binding protein, the nuclear factor κ‐light chain‐enhancer of activated B cells, c‐fos, and c‐myc. These transcription factors associate SOCE with a plethora of signaling events and cellular functions. Here we provide an overview of the current knowledge about the role of Orai channels in the regulation of transcription factors through Ca2+‐dependent signaling pathways.

Contribution of membrane-associated oscillators to biological timing at different timescales

“…Several pathways have been identified in circadian clock neurons that demonstrate how these membrane-dependent rhythms in Ca 2+ and cAMP levels couple to the molecular clockwork in the nucleus ( Figure 5 ): Different Ca 2+ - and cAMP-dependent kinase pathways modify relevant transcription factors such as CREB, thereby phase-locking second messenger oscillations to the core TTFL clockwork oscillation ( Harvey et al, 2020 ; Parnell et al, 2021 ). These signaling pathways connect plasma membrane-dependent activity with transcriptional control in the nucleus and are employed in many processes of homeostatic plasticity that stabilize ultradian spiking patterns of neurons ( Turrigiano, 2012 ; Steven et al, 2020 ; Wu et al, 2021 ; Fitzpatrick and Kerschensteiner, 2023 ; Nieto-Felipe et al, 2023 ).…”

“…Furthermore, elevated intracellular Ca 2+ activates pumps that transport Ca 2+ out of the neuron or into intracellular Ca 2+ stores such as the endoplasmatic reticulum. This intracellular store contains Ca 2+ -conducting IP 3 receptors and ryanodine-type ion channels which open in tight cooperation with plasma membrane Ca 2+ channels when intracellular Ca 2+ concentrations drop below the homeostatic setpoint and need to be restored (Duchen, 2000;Rizzuto et al, 2004;Sundararaj et al, 2021;Centeno et al, 2023;Nieto-Felipe et al, 2023). are characteristic for endogenous oscillators and clocks that control neuronal activity at the single cell level as well as at the level of neuronal networks (Debanne and Inglebert, 2023;Xiong and Garfinkel, 2023).…”

“…Hence, the increase in intracellular Ca 2+ concentration can both directly or indirectly activate and inactivate additional ion channels, which adds layers of complexity to the membrane potential oscillations ( Figures 3B, C ). Because prolonged high intracellular Ca 2+ concentrations are highly toxic to neurons, intracellular Ca 2+ levels are under tight autonomous homeostatic control ( Duchen, 2000 ; Rizzuto et al, 2004 ; Sundararaj et al, 2021 ; Centeno et al, 2023 ; Nieto-Felipe et al, 2023 ).…”

Contribution of membrane-associated oscillators to biological timing at different timescales

“…Hence, the increase in intracellular Ca 2+ concentration can both directly or indirectly activate and inactivate additional ion channels, which adds layers of complexity to the membrane potential oscillations (Fig 3B , C). Because prolonged high intracellular Ca 2+ concentrations are highly toxic to neurons, intracellular Ca 2+ levels are under tight autonomous homeostatic control (Duchen, 2000;Rizzuto et al, 2004;Sundararaj et al, 2021;Centeno et al, 2023;Nieto-Felipe et al, 2023).…”

“…Furthermore, elevated intracellular Ca 2+ activates pumps that transport Ca 2+ out of the neuron or into intracellular Ca 2+ stores such as the endoplasmatic reticulum. This intracellular store contains Ca 2+ -conducting IP3 receptors and ryanodine-type ion channels which open in tight cooperation with plasma membrane Ca 2+ channels when intracellular Ca 2+ concentrations drop below the homeostatic setpoint and need to be restored (Duchen, 2000;Rizzuto et al, 2004;Sundararaj et al, 2021;Centeno et al, 2023;Nieto-Felipe et al, 2023).…”