Cell-specific Behavior of P2X7 Receptors in Mouse Parotid Acinar and Duct Cells

Li, Qin; Luo, Xiang; Zeng, Weizhong; Muallem, Shmuel

doi:10.1074/jbc.m308306200

Cited by 57 publications

(74 citation statements)

References 34 publications

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“…Future studies should be directed to determine the relationship, if any, between P2X 4 and P2X 7 homo-and heterotrimers in salivary gland function. P2X 7 receptors have been previously localized to the apical membrane of mouse parotid acinar and duct cells (8). P2X 7 receptor immunostaining was also noted in mouse SMG duct cells, which suggests that this ligand-gated channel may participate in modification of the electrolyte content (31).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of these receptors increases [Ca 2ϩ ] i suggesting a possible role for P2 receptors in fluid secretion (4,7,8,10,18,19), although this has never been directly tested. Here we show that purinergic stimulation results in a sustained, extracellular Ca 2ϩ -dependent secretion of saliva in an intact mouse submandibular salivary gland preparation.…”

Section: Discussionmentioning

confidence: 99%

“…P2Y receptors increase [Ca 2ϩ ] i via InsP 3 -induced Ca 2ϩ mobilization from intracellular stores (similar to ␣-adrenergic and muscarinic receptors) while P2X receptors act as ligand-gated, non-selective cation channels that mediate extracellular Ca 2ϩ influx (6). Salivary gland tissues express at least four isoforms of P2X (P2X 4 and P2X 7 ) and P2Y (P2Y 1 and P2Y 2 ) subtypes; however, their in vivo physiological significance has yet to be characterized (7)(8)(9)(10)(11).…”

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confidence: 99%

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Purinergic P2X7 Receptors Mediate ATP-induced Saliva Secretion by the Mouse Submandibular Gland

Nakamoto

Brown

Catalán

et al. 2009

Journal of Biological Chemistry

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Salivary glands express multiple isoforms of P2X and P2Y nucleotide receptors, but their in vivo physiological roles are unclear. P2 receptor agonists induced salivation in an ex vivo submandibular gland preparation. The nucleotide selectivity sequence of the secretion response was BzATP Ͼ Ͼ ATP > ADP Ͼ Ͼ UTP, and removal of external Ca 2؉ dramatically suppressed the initial ATP-induced fluid secretion (ϳ85%). Together, these results suggested that P2X receptors are the major purinergic receptor subfamily involved in the fluid secretion process. Mice with targeted disruption of the P2X 7 gene were used to evaluate the role of the P2X 7 receptor in nucleotide-evoked fluid secretion. P2X 7 receptor protein and BzATPactivated inward cation currents were absent, and importantly, purinergic receptor agonist-stimulated salivation was suppressed by more than 70% in submandibular glands from P2X 7 -null mice. Consistent with these observations, the ATP-induced increases in [Ca 2؉ ] i were nearly abolished in P2X 7 ؊/؊ submandibular acinar and duct cells. ATP appeared to also act through the P2X 7 receptor to inhibit muscarinic-induced fluid secretion. These results demonstrate that the ATP-sensitive P2X 7 receptor regulates fluid secretion in the mouse submandibular gland.Salivation is a Ca 2ϩ -dependent process (1, 2) primarily associated with the neurotransmitters norepinephrine and acetylcholine, release of which stimulates ␣-adrenergic and muscarinic receptors, respectively. Both types of receptors are coupled to G proteins that activate phospholipase C␤ (PLC␤) during salivary gland stimulation. PLC␤ activation cleaves phosphatidylinositol 1,4-bisphosphate resulting in diacylglycerol and inositol 1,4,5-trisphosphate (InsP 3 ) production. Activation of Ca 2ϩ -selective InsP 3 receptor channels localized to the endoplasmic reticulum of salivary acinar cells increases the intracellular free calcium concentration ([Ca 2ϩ ] i ). 4 Depletion of the endoplasmic reticulum Ca 2ϩ pool triggers extracellular Ca 2ϩ influx and a sustained elevation in [Ca 2ϩ ] i . This increase in [Ca 2ϩ ] i activates Ca 2ϩ -dependent K ϩ and Cl Ϫ channels promoting Cl Ϫ secretion across the apical membrane and a lumen negative, electrochemical gradient that supports Na ϩ efflux into the lumen. The accumulation of NaCl creates an osmotic gradient which drives water movement into the lumen, thus generating isotonic primary saliva. This primary fluid is then modified by the ductal system, which reabsorbs NaCl and secretes KHCO 3 producing a final saliva that is hypotonic (1, 2).Salivation also has a non-cholinergic, non-adrenergic component, the origin of which is unclear (3). In addition to muscarinic and ␣-adrenergic receptors, salivary acinar cells express other receptors that are coupled to an increase in [Ca 2ϩ ] i such as purinergic P2 and substance P receptors. Like muscarinic and ␣-adrenergic receptors, P2 receptor activation leads to a sustained increase in [Ca 2ϩ ] i in salivary acinar cells (4). In contrast, substance P receptor ac...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Purinergic P2X7 Receptors Mediate ATP-induced Saliva Secretion by the Mouse Submandibular Gland

Nakamoto

Brown

Catalán

et al. 2009

Journal of Biological Chemistry

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“…It has been reported recently that P2X 7 receptors are expressed in central and spinal cord neurons [19][20][21][22]. Brain glial cells (microglia, astrocytes, and Muller cells), bone cells (osteoblasts, osteoclasts, and osteocytes), and epithelial and endothelial cells are also rich in P2X 7 receptors [23][24][25][26][27][28][29]. Expression of P2X 7 receptors has also been demonstrated in the enteric nervous system of the small intestine, kidney, urinary tract, uterus, and liver [30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of a novel variant of the human P2X7 receptor resulting in gain of function

Sun

Chu

Singh

et al. 2009

Purinergic Signalling

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The P2X 7 receptor exhibits significant allelic polymorphism in humans, with both loss and gain of function variants potentially impacting on a variety of infectious and inflammatory disorders. At least five loss-offunction polymorphisms (G150R, R307Q, T357S, E496A, and I568N) and two gain-of-function polymorphisms (H155Y and Q460R) have been identified and characterized to date. In this study, we used RT-PCR cloning to isolate and characterize P2X 7 cDNA clones from human PBMCs and THP-1 cells. A previously unreported variant with substitutions of V80M and A166G was identified. When expressed in HEK293 cells, this variant exhibited heightened sensitivity to the P2X 7 agonist (BzATP) relative to the most frequent allele, as shown by pore formation measured by fluorescent dye uptake into cells. Mutational analyses showed that A166G alteration was critical for the gain-offunction change, while V80M was not. Full-length variants with multiple previously identified nonsynonymous SNPs (H155Y, H270R, A348T, and E496A) were also identified. Distinct functional phenotypes of the P2X 7 variants or mutants constructed with multiple polymorphisms were observed. Gain-of-function variations (A166G or H155Y) could not rescue the loss-of-function E496A polymorphism. Synergistic effects of the gain-of-function variations were also observed. We also identified the A348T alteration as a weak gain-of-function variant. Thus, these results identify the new gain-of-function variant A166G and demonstrate that multiple-gene polymorphisms contribute to functional phenotypes of the human P2X 7 receptor.Furthermore, the results demonstrate that the C-terminal of the cysteine-rich domain 1 of P2X 7 is critical for regulation of P2X 7 -mediated pore formation.

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“…However, in this case, a complicating factor may be the reported ability of P2X7 receptors to interact with several cytoskeletal proteins including actin [12,45]. Actin filament disintegration, such as that occurring during the mechanical dissociation, may influence the activity of these receptors, potentially by impeding their assembly from monomers into the operative trimeric configuration [46]. The stimulation of astrocytic P2X7 receptors may lead to the release of glutamate [39], ATP [40], endocannabinoids [47], and interleukin 1-β [41,48].…”

Section: Discussionmentioning

confidence: 99%

Potentiation of the glutamatergic synaptic input to rat locus coeruleus neurons by P2X7 receptors

Khakpay

Polster

Köles

et al. 2010

Purinergic Signalling

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Locus coeruleus (LC) neurons in a rat brain slice preparation were superfused with a Mg 2+ -free and bicuculline-containing external medium. Under these conditions, glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs) were recorded by means of the whole-cell patch-clamp method. ATP, as well as its structural analogue 2-methylthio ATP (2-MeSATP), both caused transient inward currents, which were outlasted by an increase in the frequency but not the amplitude of the sEPSCs. PPADS, but not suramin or reactive blue 2 counteracted both effects of 2-MeSATP. By contrast, α,β-methylene ATP (α,β-meATP), UTP and BzATP did not cause an inward current response. Of these latter agonists, only BzATP slightly facilitated the sEPSC amplitude and strongly potentiated its frequency. PPADS and Brilliant Blue G, as well as fluorocitric acid and aminoadipic acid prevented the activity of BzATP. Furthermore, BzATP caused a similar facilitation of the miniature (m)EPSC (recorded in the presence of tetrodotoxin) and sEPSC frequencies (recorded in its absence). Eventually, capsaicin augmented the frequency of the sEPSCs in a capsazepine-, but not PPADS-antagonizable, manner. In conclusion, the stimulation of astrocytic P2X7 receptors appears to lead to the outflow of a signalling molecule, which presynaptically increases the spontaneous release of glutamate onto LC neurons from their afferent fibre tracts. It is suggested, that the two algogenic compounds ATP and capsaicin utilise separate receptor systems to potentiate the release of glutamate and in consequence to increase the excitability of LC neurons.

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Cell-specific Behavior of P2X7 Receptors in Mouse Parotid Acinar and Duct Cells

Cited by 57 publications

References 34 publications

Purinergic P2X7 Receptors Mediate ATP-induced Saliva Secretion by the Mouse Submandibular Gland

Purinergic P2X7 Receptors Mediate ATP-induced Saliva Secretion by the Mouse Submandibular Gland

Identification and characterization of a novel variant of the human P2X7 receptor resulting in gain of function

Potentiation of the glutamatergic synaptic input to rat locus coeruleus neurons by P2X7 receptors

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