The P2Y purinoceptor in rat brain microvascular endothelial cells couple to inhibition of adenylate cyclase

Webb, Tania E.; Feolde, Erick; Vigne, Paul; Neary, Joseph T.; Runberg, Anna; Frelin, Christian; Barnard, Eric A.

doi:10.1111/j.1476-5381.1996.tb16050.x

Cited by 97 publications

(106 citation statements)

References 49 publications

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“…However, doubts still remained as to whether the P2Y 1 receptor might be coupled to adenylyl cyclase inhibition, at least in native cells (35). Functional studies of platelets from P2Y 1 -/-mice demonstrated a loss of ADP-induced aggregation, firmly establishing the requirement for this receptor for ADP-induced platelet aggregation (Figure 2).…”

Section: Discussionmentioning

confidence: 97%

Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor–null mice

Léon¹,

Hechler²,

Freund³

et al. 1999

J. Clin. Invest.

425

399

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Section: Discussionmentioning

confidence: 97%

Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor–null mice

Léon¹,

Hechler²,

Freund³

et al. 1999

J. Clin. Invest.

425

399

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“…The B10 cells respond to extracellular adenine (but not uracil) nucleotides with intracellular Ca 2ϩ mobilization, mediated by a G-protein-coupled P2Y 1 receptor (2). Whereas the known rat P2Y 1 receptor cDNA could be isolated from the B10 cells (2), no transcript for any other then-known P2Y receptor subtype was detectable in them.…”

mentioning

confidence: 99%

Characterization and Channel Coupling of the P2Y12Nucleotide Receptor of Brain Capillary Endothelial Cells

Simon¹,

Filippov²,

Göransson³

et al. 2002

Journal of Biological Chemistry

Self Cite

103

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B10 cells are an endothelial clonal line derived spontaneously by culture and selection of rat brain microvascular endothelial cells (1), a source of considerable pharmacological potential. The B10 cells respond to extracellular adenine (but not uracil) nucleotides with intracellular Ca 2ϩ mobilization, mediated by a G-protein-coupled P2Y 1 receptor (2). Whereas the known rat P2Y 1 receptor cDNA could be isolated from the B10 cells (2), no transcript for any other then-known P2Y receptor subtype was detectable in them. However, the B10 cells were found to exhibit another second messenger response, namely the inhibition of stimulated adenylyl cyclase, but with a nucleotide agonist specificity very similar to that of the P2Y 1 receptor (2). It was further demonstrated (3) that selective antagonists of the P2Y 1 receptor, such as adenosine 3Ј-phosphate 5Ј-phosphate, were unable to affect that response, although it showed high sensitivity to 2-propylthio-D-␤,␥-difluoromethylene-ATP (AR-C66096), 1 a specific antagonist (4, 5) of the adenylyl cyclase-inhibitory P2Y T or "P2T" receptor for ADP, which was known as an important functional component of blood platelets. That study (3) demonstrated that a second P2Y receptor activity is present in the B10 cell, with some of its functional features in common with the platelet P2Y T receptor.Recently, a cDNA encoding a nucleotide receptor with a novel seven-transmembrane sequence was identified independently by two groups, starting from a human platelet cDNA library or an orphan human DNA sequence, and shown to be distantly but significantly related to the known P2Y receptors (6, 7). This was designated as the P2Y 12 receptor. Its amino acid sequence lies on a previously unrecognized separate branch of the P2Y family (8). It was characterized in both studies to show its adenine nucleotide specificity and its inhibition of forskolin-stimulated adenylyl cyclase, in which it corresponds to the platelet P2Y T receptor (6, 7). That human P2Y 12 receptor cDNA was expressed again in cell line hosts by other groups, confirming the reported series of agonists but with higher potencies in the cAMP decrease (9) and showing their affinities by competition with the binding of radiolabeled 2-MeSADP (9, 10). In the original identification of the human P2Y 12 receptor, a similar cDNA was also derived from a rat platelet library (6), and its RNA was shown to express in Xenopus oocytes, but this receptor was not further characterized.The question, therefore, obviously arises as to whether the cyclase inhibitory receptor for adenine nucleotides of the B10 capillary endothelial cell is in fact the P2Y 12 receptor. However, this cannot necessarily be assumed, because the P2T receptor has commonly been described in the literature as specific to the platelet (11,12). Furthermore, the adenylyl cyclase-inhibitory P2Y receptor activity in the B10 cell differs in an important

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“…Furthermore, P2Y 1 Rs can exert cellular effects that are quite different from those exerted by other P2YRs expressed in the same cell type and that couple to similar G proteins. For example, in astrocytes, both P2Y 1 Rs and P2Y 2 Rs can couple by means of G q to the release of Ca 2ϩ from a common intracellular pool (16). Yet, P2Y 1 Rs and P2Y 2 Rs exhibit striking temporal differences in their Ca 2ϩ response patterns and susceptibility to regulation by PKC (17).…”

mentioning

confidence: 99%

“…For example, in astrocytes, both P2Y 1 Rs and P2Y 2 Rs can couple by means of G q to the release of Ca 2ϩ from a common intracellular pool (16). Yet, P2Y 1 Rs and P2Y 2 Rs exhibit striking temporal differences in their Ca 2ϩ response patterns and susceptibility to regulation by PKC (17). At present, it is not clear why P2Y 1 R activity is so dependent on cellular context or why P2Y 1 Rs can exert physiological effects that are so different from related P2YR subtypes.…”

mentioning

confidence: 99%

“…Most P2YRs are coupled to G␣ q proteins and thus to the activation of phospholipase C␤ (PLC␤) and generation of diacylglycerol and inositol-3,4,5-trisphosphate, ultimately leading to the activation of PKC and release of Ca 2ϩ from internal stores (1). Some P2YRs, including P2Y 1 , P2Y 2 , P2Y 12 , and P2Y 13 , are also known to couple to G␣ i and the inhibition of adenylyl cyclase (2)(3)(4)(5). The purinergic P2YR type 1 (P2Y 1 R) subtype is abundantly expressed in a number of tissues, including the CNS (6,7), where it plays a key role in the transmission of astrocytic Ca 2ϩ waves (8), activation of mitogenic responses in astrocytes to brain trauma (9), inhibition of neuronal N-type voltage-activated Ca 2ϩ channels (10), and embryonic brain development (11).…”

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confidence: 99%

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P2Y ₁ receptor signaling is controlled by interaction with the PDZ scaffold NHERF-2

Fam

Paquet

Castleberry

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

119

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P2Y1 purinergic receptors (P2Y1Rs) mediate rises in intracellular Ca 2؉ in response to ATP, but the duration and characteristics of this Ca 2؉ response are known to vary markedly in distinct cell types. We screened the P2Y1R carboxyl terminus against a recently created proteomic array of PDZ (PSD-95͞Drosophila Discs large͞ZO-1 homology) domains and identified a previously unrecognized, specific interaction with the second PDZ domain of the scaffold NHERF-2 (Na ؉ ͞H ؉ exchanger regulatory factor type 2). Furthermore, we found that P2Y1R and NHERF-2 associate in cells, allowing NHERF-2-mediated tethering of P2Y 1R to key downstream effectors such as phospholipase C␤. Finally, we found that coexpression of P2Y1R with NHERF-2 in glial cells prolongs P2Y1R-mediated Ca 2؉ signaling, whereas disruption of the P2Y1R-NHERF-2 interaction by point mutations attenuates the duration of P2Y1R-mediated Ca 2؉ responses. These findings reveal that NHERF-2 is a key regulator of the cellular activity of P2Y 1R and may therefore determine cellspecific differences in P2Y1R-mediated signaling.G protein-coupled receptor ͉ purinergic ͉ ATP ͉ proteomic array A denine-based nucleotides such as ATP and ADP are prominent extracellular signaling molecules that mediate a wide variety of physiological actions in tissues throughout the body. Many of the physiological effects evoked by ATP and ADP are mediated by metabotropic P2Y receptors (P2YRs) (1), which are members of the G protein-coupled receptor (GPCR) superfamily. To date, seven distinct mammalian P2YR subtypes have been cloned: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , and P2Y 13 . Most P2YRs are coupled to G␣ q proteins and thus to the activation of phospholipase C␤ (PLC␤) and generation of diacylglycerol and inositol-3,4,5-trisphosphate, ultimately leading to the activation of PKC and release of Ca 2ϩ from internal stores (1). Some P2YRs, including P2Y 1 , P2Y 2 , P2Y 12 , and P2Y 13 , are also known to couple to G␣ i and the inhibition of adenylyl cyclase (2-5). The purinergic P2YR type 1 (P2Y 1 R) subtype is abundantly expressed in a number of tissues, including the CNS (6, 7), where it plays a key role in the transmission of astrocytic Ca 2ϩ waves (8), activation of mitogenic responses in astrocytes to brain trauma (9), inhibition of neuronal N-type voltage-activated Ca 2ϩ channels (10), and embryonic brain development (11). P2Y 1 R also plays critical roles in the cardiovascular system, including the regulation of coronary vasodilation (12) and platelet aggregation (13).Signaling by P2Y 1 Rs is known to be heavily dependent on cellular context. For example, stimulation of P2Y 1 Rs in some cell types is known to strongly promote cell proliferation (14), whereas P2Y 1 R stimulation in other cell types is known to induce apoptosis (15). Furthermore, P2Y 1 Rs can exert cellular effects that are quite different from those exerted by other P2YRs expressed in the same cell type and that couple to similar G proteins. For example, in astrocytes, both P2Y 1 Rs and P2Y 2 Rs can cou...

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The P2Y purinoceptor in rat brain microvascular endothelial cells couple to inhibition of adenylate cyclase

Cited by 97 publications

References 49 publications

Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor–null mice

Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor–null mice

Characterization and Channel Coupling of the P2Y12Nucleotide Receptor of Brain Capillary Endothelial Cells

P2Y ₁ receptor signaling is controlled by interaction with the PDZ scaffold NHERF-2

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The P2Y purinoceptor in rat brain microvascular endothelial cells couple to inhibition of adenylate cyclase

Cited by 97 publications

References 49 publications

Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor–null mice

Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor–null mice

Characterization and Channel Coupling of the P2Y12Nucleotide Receptor of Brain Capillary Endothelial Cells

P2Y 1 receptor signaling is controlled by interaction with the PDZ scaffold NHERF-2

Contact Info

Product

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About

P2Y ₁ receptor signaling is controlled by interaction with the PDZ scaffold NHERF-2