Role of the store-operated Ca𝟐+ channel in ATP-induced Ca𝟐+ signalling in mesenchymal stem cells and regulation of cell functions

¹ Department of Physiology and Pathophysiology and Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Xinxiang Medical University, 453003 Xinxiang, Henan, China

² EA4245-Transplantation, Immunology and Inflammation, Faculty of Medicine, University of Tours, 37032 Tours, France

³ Division of Oral Biology, University of Leeds, Welcome Trust Brenner Building, LS9 7TF Leeds, UK

⁴ School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT Leeds, UK

^*Correspondence: l.h.jiang@leeds.ac.uk (Lin-Hua Jiang)
Academic Editor: Graham Pawelec

Front. Biosci. (Landmark Ed) 2021, 26(12), 1737–1745; https://doi.org/10.52586/5065

Submitted: 16 September 2021 | Revised: 13 October 2021 | Accepted: 22 October 2021 | Published: 30 December 2021

(This article belongs to the Special Issue Twenty-five years at the frontiers of knowledge: a quarter-century of "Frontiers in Bioscience")

This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

Abstract

It is well-known that extracellular ATP acts as an autocrine/paracrine signal to regulate cell functions by inducing intracellular Ca ${}^{2+}$ signalling through its cognate receptors, namely, the ligand-gated ion channel P2X receptors that mediate Ca ${}^{2+}$ influx and/or the G ${}_{q/11}$ -coupled P2Y receptors that link to Ca ${}^{2+}$ release from the ER. The reduction in ER Ca ${}^{2+}$ can trigger further extracellular Ca ${}^{2+}$ entry by activating the store-operated Ca ${}^{2+}$ (SOC) channel. Mesenchymal stem cells (MSC) play an important role in the homeostasis of residing tissues and have promising applications in regenerative medicines. MSC can release ATP spontaneously or in response to diverse stimuli, and express multiple P2X and G ${}_{q/11}$ -coupled P2Y receptors that participate in ATP-induced Ca ${}^{2+}$ signalling and regulate cell function. There is increasing evidence to show the contribution of the SOC channel in ATP-induced Ca ${}^{2+}$ signalling in MSC. In this mini-review, we discuss the current understanding of the expression of the SOC channel in MSC and its potential role in mediating ATP-induced Ca ${}^{2+}$ signalling and regulation of MSC differentiation, proliferation and migration.

Keywords

Mesenchymal stem cells

Extracellular ATP

Ca²⁺ signalling

Store-operated Ca²⁺ channel

Figures

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Fig. 1.

A graphic illustration of the molecular mechanisms that participate in ATP-induced Ca ${}^{\bm{2+}}$ signalling in mesenchymal stem cells (MSC). (A) Extracellular ATP induces an increase in intracellular Ca ${}^{2+}$ concentration via the P2X7 receptor that mediates Ca ${}^{2+}$ influx (i). Alternatively, ATP activates the G ${}_{q/11}$ -coupled P2Y receptor (P2Y ${}_{1}$ , P2Y ${}_{2}$ and/or P2Y ${}_{11}$ ) and phospholipase C (PLC) to generate inositol 1,4,5-triphosphate (IP ${}_{3}$ ) from membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP ${}_{2}$ ) and induce IP ${}_{3}$ receptor (IP ${}_{3}$ R)-mediated Ca ${}^{2+}$ release from the endoplasmic reticulum (ER) (ii). Release of the ER Ca ${}^{2+}$ subsequently triggers store-operated Ca ${}^{2+}$ entry (SOCE) through the store-operated Ca ${}^{2+}$ (SOC) channel, particularly the Ca ${}^{2+}$ -release-activated Ca ${}^{2+}$ (CRAC) channel (iii). Inhibition of the sarcoplasmic/endoplasmic Ca ${}^{2+}$ -ATPase (SERCA) with thapsigargin (TG) to prevent the cytosolic Ca ${}^{2+}$ uptake can lead to loss of the ER Ca ${}^{2+}$ , which is widely used in “Ca ${}^{2+}$ add-back” experiments to activate the SOC channel. (B) Example recordings using “Ca ${}^{2+}$ add-back” to show that treatment of human dental pulp-derived MSC with TG induced release of the ER Ca ${}^{2+}$ in the absence of extracellular Ca ${}^{2+}$ led to a greater Ca ${}^{2+}$ response upon re-introduction of extracellular Ca ${}^{2+}$ . CTL, control (without TG treatment). (C) Example recordings showing that small interference RNA (siRNA)-mediated knockdown of the expression of Orai1 or Stim1 reduced ATP-induced Ca ${}^{2+}$ response in human dental pulp MSC. Scr-siRNA, scrambled siRNA. (B) and (C) taken and modified from Peng et al. (2016) [80].

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