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Contribution of Purinergic Receptors to Calcium Signaling in Salivary Gland

Bhattacharya, Sumit
http://rave.ohiolink.edu/etdc/view?acc_num=mco1353370433

Abstract Details

2012, Doctor of Philosophy (PhD), University of Toledo, College of Medicine.
There is emerging consensus that P2X4 and P2X7 ionotropic purinoceptors (P2X4R and P2X7R) are critical players in regulating [Ca2+]i dynamics and fluid secretion in the salivary gland. In contrast, details regarding their compartmentalization and selective activation, contributions to the spatiotemporal properties of intracellular signals and roles in regulating protein exocytosis and ion channel activity have remained largely undefined. Moreover, information regarding modulation of P2X class of receptors by cAMP, the major purinergic cell signaling pathway for protein secretion has been limited. To address these gaps in our understanding, we profiled mouse parotid acinar cells using live-cell imaging to follow the spatial and temporal features of ATP-evoked Ca2+ dynamics and exocytotic activity. Selective activation of P2X7Rs revealed an apical-to-basal [Ca2+]i signal that initiated at the sub-luminal border and propagated with a wave speed estimated at 17.3 ± 4.3 μm/s (n = 6). The evoked Ca2+ spike consisted of Ca2+ influx and Ca2+-induced Ca2+ release from intracellular Ca2+ channels. In contrast, selective activation of P2X4Rs induced a Ca2+ signal that initiated basally and propagated toward the lumen with a wave speed of 4.3 ± 0.2 μm/s (n = 8) that was largely independent of intracellular Ca2+ channel blockade. Consistent with these observations, P2X7R expression was enriched in the sub-luminal regions of acinar cells while P2X4R appeared localized to basal areas. We also predict that P2X7R enriching the apical regions of acinar cells are activated by luminal ATP. We also showed that P2X4R and P2X7R activation evokes exocytosis in parotid acinar cells. Our studies also demonstrate that the P2X4R-mediated [Ca2+]i rise and subsequent protein exocytosis was enhanced by ivermectin (IVR) thereby making it a potential target treatment of salivary hypofunction diseases. Additionally, experiments designed to assess crosstalk between purinoceptors (P2X4R and P2X7R) and cAMP signaling pathways showed that [Ca2+]i levels were enhanced upon β-adrenergic receptor stimulation or during rises in intracellular cAMP levels by synthetic cAMP agonists. The current study supports the notion that PKA dependent crosstalk between purinoceptors evoked Ca2+ signals and cAMP pathway might be critical in regulation of both fluid and protein secretion in parotid acinar cells. Thus crosstalk between the two signaling pathways can also be exploited for construction of therapies associated with salivary hypofunction.
David Giovannucci, PhD (Advisor)
Joseph Margiotta, PhD (Committee Member)
Kathryn Eisenmann, PhD (Committee Member)
Joshua Park, PhD (Committee Member)
Guillermo Vazquez, PhD (Committee Member)
113 p.
Biology; Neurobiology; Neurology; Neurosciences; Pharmacology; Physiology
ATP; purinergic; exocytosis; calcium; p2x4; p2x7; saliva; parotid; acinar cells; cAMP

Recommended Citations

Citations

  • Bhattacharya, S. (2012). Contribution of Purinergic Receptors to Calcium Signaling in Salivary Gland [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1353370433

    APA Style (7th edition)

  • Bhattacharya, Sumit. Contribution of Purinergic Receptors to Calcium Signaling in Salivary Gland. 2012. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1353370433.

    MLA Style (8th edition)

  • Bhattacharya, Sumit. "Contribution of Purinergic Receptors to Calcium Signaling in Salivary Gland." Doctoral dissertation, University of Toledo, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=mco1353370433

    Chicago Manual of Style (17th edition)

mco1353370433
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© 2012, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.