Crosstalk between purinergic receptors and canonical signaling pathways in the mouse salivary gland

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

“…In contrast, studies using human parotid acinar cells found this co-stimulatory effect only between the P2X4R and β-adrenergic receptor (Brown et al, 2004). Taken together, the expression of both P2X7Rs and P2X4Rs in salivary glands supports the idea that they are involved in the interplay between canonical and non-canonical signaling pathways that regulate saliva flow and composition and their involvement is likely dependent on their tissue localization (i.e., basal vs. apical) in polarized acinar and/or ductal epithelial cells (Bhattacharya et al, 2012(Bhattacharya et al, , 2015.…”

“…While the contribution of P2X4R activation to physiological saliva production has not been explored, ex vivo murine SMG preparations from P2X7R −/− mice exhibit weak ATP-induced saliva secretion that could be attributed to P2X4R activation (Nakamoto et al, 2009). As seen previously with muscarinic or adrenergic receptor activation (Baldys-Waligorska et al, 1987;Yoshimura and Hiramatsu, 1998;Tanimura et al, 1999;Bruce et al, 2002), co-stimulation of β-adrenergic receptors and P2X7Rs or P2X4Rs enhanced the influx of Ca 2+ in mouse parotid acinar cells, as compared to activation of either receptor alone (Bhattacharya et al, 2015). In contrast, studies using human parotid acinar cells found this co-stimulatory effect only between the P2X4R and β-adrenergic receptor (Brown et al, 2004).…”

“…In addition to the canonical M 3 R and β-AR pathways, a mechanism of non-cholinergic, non-adrenergic-mediated salivary flow exists (Ekström et al, 1988;Ekström, 1999;Melvin et al, 2005). Because purinergic receptor activation can result in an increase in [Ca 2+ ] i in salivary gland cells, purinergic receptor-mediated saliva production may contribute to this non-canonical pathway (Turner et al, 1998b;Melvin et al, 2005;Aure et al, 2010;Bhattacharya et al, 2015).…”

“…Studies indicate no difference in [Na + ] or [Cl − ] in muscarinic agonist-induced whole saliva secreted in wild type compared to P2X7R −/− mice, however the [K + ] was elevated in P2X7R −/− mouse whole saliva (Pochet et al, 2007). Since the majority of the K + in saliva originates from ductal cells, it has been hypothesized that ATP released from acinar cells during exocytosis stimulates ductal P2X7Rs that regulate the activity of K + channels located on the apical membrane Bhattacharya et al, 2015). In addition to K + modification, activation of P2X7Rs in ductal cells increases phospholipase A2-dependent secretion of arachidonic acid, a precursor of prostaglandin E2 (PGE 2 ), and kallikrein (Alzola et al, 1998) into saliva (Pantano et al, 2019).…”

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

“…In isolated clusters of mouse parotid acinar cells, activation of ␤-adrenergic receptor enhances P2X4R-or P2X7R-mediated intracellular calcium influx. Although the augmentation of P2X4R-evoked Ca 2ϩ signals by cAMP modulators is largely mediated by PKA, as the selective PKA-inhibitor PKI abolishes this effect, enhancement of Ca 2ϩ changes by EPAC activation with 007 suggests a potential function for EPAC in P2XR signaling (79). Such a notion is consistent with the finding that isoproterenol-stimulated amylase secretion occurs via both an AKAP5/AC6/PKA complex and a PKA-independent, EPAC pathway in mouse parotid acini (1130).…”