Fig. 1.

Schematic diagram illustrating the molecular mechanisms for ATP release and hydrolysis, and ATP-induced Ca²⁺ signalling in MSC. MSC release ATP constitutively through connexin (Cx) hemi-channels and in response to mechanical stimuli via vesicular exocytosis. Extracellular ATP are hydrolyzed to ADP and AMP by ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) and ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP) and further to adenosine (Ade) by ecto-5′-nucelotidase (E-NT). Once outside the cell, ATP acts as an autocrine or paracrine signalling molecule by elevating the cytosolic Ca²⁺ concentrations ([Ca²⁺]_c) through three molecular mechanisms. ATP can induce activation of the P2X7 receptor ion channel allowing extracellular Ca²⁺ influx. Alternatively, ATP can activate the P2Y₁, P2Y₂ and/or P2Y₁₁ receptor, leading to sequential activation of G_α,q/11, phospholipase C (PLC), conversion of membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP₂) to inositol triphosphate (IP₃) and diacylglycerol (DAG), activation of the receptor for IP₃ (IP₃R) and Ca²⁺ release from the endoplasmic reticulum (ER). Depletion of the ER Ca²⁺, upon activation of the G_α,q/11-PLC-IP₃R signalling pathway or blockage of the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) induces extracellular Ca²⁺ entry via the store-operated Ca²⁺ (SOC) or Ca²⁺ release activated Ca²⁺ (CRAC) channel. Stim1 acts as the ER Ca²⁺ sensor via the EF-hand motifs located in the ER lumen (denoted by yellow strip) to monitor the ER Ca²⁺ level. Reduction in the ER Ca²⁺ level induces conformal changes in Stim1, leading to its translocation to and trapping at the ER-plasma membrane junction, where it interacts with the Orai1 protein to open the Ca²⁺-permeating channel. Further details and references are described in the text. The structural features of the P2X7 receptor, Orai1 channel and P2Y receptor are illustrated on the right