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  1. Article ; Online: A mechanism for nerve cell excitation by norepinephrine via α-1 adrenoceptors: inhibition of potassium M-current.

    Filippov, Alexander K / Brown, David A

    Cellular and molecular neurobiology

    2012  Volume 33, Issue 1, Page(s) 1–4

    Abstract: Some of the excitatory effects of norepinephrine on central neurons are mediated by alpha-1 (α1) adrenoceptors. These receptors are coupled to the Gq family of G proteins, and hence stimulate hydrolysis of the membrane phospholipid phosphatidylinositol-4, ...

    Abstract Some of the excitatory effects of norepinephrine on central neurons are mediated by alpha-1 (α1) adrenoceptors. These receptors are coupled to the Gq family of G proteins, and hence stimulate hydrolysis of the membrane phospholipid phosphatidylinositol-4,5-bisphosphate. Other receptors of this type can excite neurons by inhibiting the subthreshold voltage-gated potassium M-current. We tested this possibility using rat sympathetic neurons transformed to express α1a receptors. The α1 agonist phenylephrine strongly inhibited the M-current recorded under voltage-clamp by 72 ± 11 % (n = 4) and in an unclamped neuron dramatically increased the number of action potentials produced by a 2 s depolarizing current step from 2 to 40, without effect on control neurons devoid of α1 receptors. We suggest that this might be a potential cause of the increased excitability produced by norepinephrine in some central neurons.
    MeSH term(s) Adrenergic alpha-1 Receptor Agonists/pharmacology ; Animals ; Cells, Cultured ; Ganglia, Sympathetic/drug effects ; Ganglia, Sympathetic/physiology ; Membrane Potentials/drug effects ; Membrane Potentials/physiology ; Neural Inhibition/drug effects ; Neural Inhibition/physiology ; Norepinephrine/physiology ; Phenylephrine/pharmacology ; Potassium Channel Blockers/pharmacology ; Potassium Channels, Voltage-Gated/antagonists & inhibitors ; Potassium Channels, Voltage-Gated/physiology ; Rats ; Receptors, Adrenergic, alpha-1/physiology
    Chemical Substances Adrenergic alpha-1 Receptor Agonists ; Potassium Channel Blockers ; Potassium Channels, Voltage-Gated ; Receptors, Adrenergic, alpha-1 ; Phenylephrine (1WS297W6MV) ; Norepinephrine (X4W3ENH1CV)
    Language English
    Publishing date 2012-08-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 283404-2
    ISSN 1573-6830 ; 0272-4340
    ISSN (online) 1573-6830
    ISSN 0272-4340
    DOI 10.1007/s10571-012-9870-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1727: Show issues Location:
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  2. Article ; Online: The scaffold protein NHERF2 determines the coupling of P2Y1 nucleotide and mGluR5 glutamate receptor to different ion channels in neurons.

    Filippov, Alexander K / Simon, Joseph / Barnard, Eric A / Brown, David A

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2010  Volume 30, Issue 33, Page(s) 11068–11072

    Abstract: Expressed metabotropic group 1 glutamate mGluR5 receptors and nucleotide P2Y1 receptors (P2Y1Rs) show promiscuous ion channel coupling in sympathetic neurons: their stimulation inhibits M-type [Kv7, K(M)] potassium currents and N-type (Ca(V)2.2) calcium ... ...

    Abstract Expressed metabotropic group 1 glutamate mGluR5 receptors and nucleotide P2Y1 receptors (P2Y1Rs) show promiscuous ion channel coupling in sympathetic neurons: their stimulation inhibits M-type [Kv7, K(M)] potassium currents and N-type (Ca(V)2.2) calcium currents (Kammermeier and Ikeda, 1999; Brown et al., 2000). These effects are mediated by G(q) and G(i/o) G-proteins, respectively. Via their C-terminal tetrapeptide, these receptors also bind to the PDZ domain of the scaffold protein NHERF2, which enhances their coupling to G(q)-mediated Ca(2+) signaling (Fam et al., 2005; Paquet et al., 2006b). We investigated whether NHERF2 could modulate coupling to neuronal ion channels. We find that coexpression of NHERF2 in sympathetic neurons (by intranuclear cDNA injections) does not affect the extent of M-type potassium current inhibition produced by either receptor but strongly reduced Ca(V)2.2 inhibition by both P2Y1R and mGluR5 activation. NHERF2 expression had no significant effect on Ca(V)2.2 inhibition by norepinephrine (via alpha(2)-adrenoceptors, which do not bind NHERF2), nor on Ca(V)2.2 inhibition produced by an expressed P2Y1R lacking the NHERF2-binding DTSL motif. Thus, NHERF2 selectively restricts downstream coupling of mGluR5 and P2Y1Rs in neurons to G(q)-mediated responses such as M-current inhibition. Differential distribution of NHERF2 in neurons may therefore determine coupling of mGluR5 receptors and P2Y1 receptors to calcium channels.
    MeSH term(s) Animals ; Calcium Channels/metabolism ; Calcium Channels, N-Type/metabolism ; Cell Line ; Cytoskeletal Proteins/genetics ; Cytoskeletal Proteins/metabolism ; GTP-Binding Protein alpha Subunits, Gq-G11/metabolism ; Humans ; In Vitro Techniques ; Ion Channels/metabolism ; Membrane Potentials/drug effects ; Neurons/drug effects ; Neurons/metabolism ; Patch-Clamp Techniques ; Potassium Channels/metabolism ; Rats ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate/metabolism ; Receptors, Purinergic P2/metabolism ; Receptors, Purinergic P2Y1 ; Sodium-Hydrogen Exchangers ; Superior Cervical Ganglion/drug effects ; Superior Cervical Ganglion/metabolism ; Transfection
    Chemical Substances Cacna1b protein, rat ; Calcium Channels ; Calcium Channels, N-Type ; Cytoskeletal Proteins ; GRM5 protein, human ; Grm5 protein, rat ; Ion Channels ; P2RY1 protein, human ; P2ry1 protein, rat ; Potassium Channels ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate ; Receptors, Purinergic P2 ; Receptors, Purinergic P2Y1 ; Slc9a3r2 protein, rat ; Sodium-Hydrogen Exchangers ; GTP-Binding Protein alpha Subunits, Gq-G11 (EC 3.6.5.1)
    Language English
    Publishing date 2010-08-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.2597-10.2010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Coupling of the nucleotide P2Y4 receptor to neuronal ion channels.

    Filippov, Alexander K / Simon, Joseph / Barnard, Eric A / Brown, David A

    British journal of pharmacology

    2003  Volume 138, Issue 2, Page(s) 400–406

    Abstract: 1. G protein-linked P2Y nucleotide receptors are known commonly to stimulate the phosphoinositide signalling pathway. However, we have previously demonstrated that the cloned P2Y(2), P2Y(6) and P2Y(1) receptors couple to neuronal N-type Ca(2+) channels ... ...

    Abstract 1. G protein-linked P2Y nucleotide receptors are known commonly to stimulate the phosphoinositide signalling pathway. However, we have previously demonstrated that the cloned P2Y(2), P2Y(6) and P2Y(1) receptors couple to neuronal N-type Ca(2+) channels and to M-type K(+) channels. Here we investigate the coupling of recombinant, neuronally expressed rat- and human P2Y(4) receptors (rP2Y(4), hP2Y(4)) to those channels. 2. Rat sympathetic neurones were nuclear-injected with a P2Y(4) cDNA plasmid. A subsequent activation of rP2Y(4) or hP2Y(4) by UTP (100 micro M) in whole-cell (ruptured-patch) mode produced only about 12% inhibition of the N-type Ca(2+) current (I(Ca(N))). Surprisingly, in perforated patch mode, UTP produced much more inhibition of I(Ca(N)) (maximally 51%), with an IC(50) value of 273 nM. This inhibition was voltage-dependent and was blocked by co-expression of the betagamma-binding transducin Galpha-subunit. Pertussis toxin (PTX) pretreatment also suppressed I(Ca(N)) inhibition. 3. UTP inhibited the M-current, recorded in perforated patch mode, by (maximally) 52%, with IC(50) values of 21 nM for rP2Y(4) and 28 nM for hP2Y(4). This inhibition was not affected by PTX pretreatment. 4. With rP2Y(4), ATP inhibited the M-current (IC(50) 524 nM, 26 times weaker than UTP), whereas ATP had no agonist activity at hP2Y(4). This suggests a difference in agonist binding site between rP2Y(4) and hP2Y(4). 5. We conclude that, in contrast to other nucleotide receptors studied, the P2Y(4) receptor couples much more effectively to M-type K(+) channels than to Ca(2+) channels. Coupling to the Ca(2+) channels involves the betagamma-subunits of G(i/o)-proteins and requires a diffusible intracellular component that is lost in ruptured-patch recording.
    MeSH term(s) Animals ; Dose-Response Relationship, Drug ; Humans ; Ion Channels/agonists ; Ion Channels/metabolism ; Membrane Potentials/drug effects ; Membrane Potentials/physiology ; Neurons/drug effects ; Neurons/metabolism ; Purinergic P2 Receptor Agonists ; Rats ; Receptors, Purinergic P2/metabolism ; Uridine Triphosphate/pharmacology
    Chemical Substances Ion Channels ; Purinergic P2 Receptor Agonists ; Receptors, Purinergic P2 ; purinoceptor P2Y4 ; Uridine Triphosphate (UT0S826Z60)
    Language English
    Publishing date 2003-01-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1038/sj.bjp.0705043
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Activation of P2Y1 nucleotide receptors induces inhibition of the M-type K+ current in rat hippocampal pyramidal neurons.

    Filippov, Alexander K / Choi, Roy C Y / Simon, Joseph / Barnard, Eric A / Brown, David A

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2006  Volume 26, Issue 36, Page(s) 9340–9348

    Abstract: We have shown previously that stimulation of heterologously expressed P2Y1 nucleotide receptors inhibits M-type K+ currents in sympathetic neurons. We now report that activation of endogenous P2Y1 receptors induces inhibition of the M-current in rat CA1/ ... ...

    Abstract We have shown previously that stimulation of heterologously expressed P2Y1 nucleotide receptors inhibits M-type K+ currents in sympathetic neurons. We now report that activation of endogenous P2Y1 receptors induces inhibition of the M-current in rat CA1/CA3 hippocampal pyramidal cells in primary neuron cultures. The P2Y1 agonist adenosine 5'-[beta-thio]diphosphate trilithium salt (ADPbetaS) inhibited M-current by up to 52% with an IC50 of 84 nM. The hydrolyzable agonist ADP (10 microM) produced 32% inhibition, whereas the metabotropic glutamate receptor 1/5 agonist DHPG [(S)-3,5-dihydroxyphenylglycine] (10 microM) inhibited M-current by 44%. The M-channel blocker XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride] produced 73% inhibition at 3 microM; neither ADPbetaS nor ADP produced additional inhibition in the presence of XE991. The effect of ADPbetaS was prevented by a specific P2Y1 antagonist, MRS 2179 (2'-deoxy-N'-methyladenosine-3',5'-bisphosphate tetra-ammonium salt) (30 microM). Inhibition of the M-current by ADPbetaS was accompanied by increased neuronal firing in response to injected current pulses. The neurons responding to ADPbetaS were judged to be pyramidal cells on the basis of (1) morphology, (2) firing characteristics, and (3) their distinctive staining for the pyramidal cell marker neurogranin. Strong immunostaining for P2Y1 receptors was shown in most cells in these cultures: 74% of the cells were positive for both P2Y1 and neurogranin, whereas 16% were only P2Y1 positive. These results show the presence of functional M-current-inhibitory P2Y1 receptors on hippocampal pyramidal neurons, as predicted from their effects when expressed in sympathetic neurons. However, the mechanism of inhibition in the two cell types seems to differ because, unlike nucleotide-mediated M-current inhibition in sympathetic neurons, that in hippocampal neurons did not appear to result from raised intracellular calcium.
    MeSH term(s) Action Potentials/physiology ; Animals ; Cells, Cultured ; Hippocampus/physiology ; Membrane Potentials/physiology ; Neural Inhibition/physiology ; Potassium/metabolism ; Potassium Channels/physiology ; Pyramidal Cells/physiology ; Rats ; Receptors, Purinergic P2/metabolism ; Receptors, Purinergic P2Y1
    Chemical Substances P2ry1 protein, rat ; Potassium Channels ; Receptors, Purinergic P2 ; Receptors, Purinergic P2Y1 ; Potassium (RWP5GA015D)
    Language English
    Publishing date 2006-09-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.2635-06.2006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Relationship between membrane phosphatidylinositol-4,5-bisphosphate and receptor-mediated inhibition of native neuronal M channels.

    Winks, Joanna S / Hughes, Simon / Filippov, Alexander K / Tatulian, Lucine / Abogadie, Fe C / Brown, David A / Marsh, Stephen J

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2006  Volume 25, Issue 13, Page(s) 3400–3413

    Abstract: The relationship between receptor-induced membrane phosphatidylinositol-4'5'-bisphosphate (PIP2) hydrolysis and M-current inhibition was assessed in single-dissociated rat sympathetic neurons by simultaneous or parallel recording of membrane current and ... ...

    Abstract The relationship between receptor-induced membrane phosphatidylinositol-4'5'-bisphosphate (PIP2) hydrolysis and M-current inhibition was assessed in single-dissociated rat sympathetic neurons by simultaneous or parallel recording of membrane current and membrane-to-cytosol translocation of the fluorescent PIP2/inositol 1,4,5-trisphosphate (IP3)-binding peptide green fluorescent protein-tagged pleckstrin homology domain of phospholipase C (GFP-PLCdelta-PH). The muscarinic receptor agonist oxotremorine-M produced parallel time- and concentration-dependent M-current inhibition and GFP-PLCdelta-PH translocation; bradykinin also produced parallel time-dependent inhibition and translocation. Phosphatidylinositol-4-phosphate-5-kinase (PI5-K) overexpression reduced both M-current inhibition and GFP-PLCdelta-PH translocation by both oxotremorine-M and bradykinin. These effects were partly reversed by wortmannin, which inhibits phosphatidylinositol-4-kinase (PI4-K). PI5-K overexpression also reduced the inhibitory action of oxotremorine-M on PIP2-gated G-protein-gated inward rectifier (Kir3.1/3.2) channels; bradykinin did not inhibit these channels. Overexpression of neuronal calcium sensor-1 protein (NCS-1), which increases PI4-K activity, did not affect responses to oxotremorine-M but reduced both fluorescence translocation and M-current inhibition by bradykinin. Using an intracellular IP3 membrane fluorescence-displacement assay, initial mean concentrations of membrane [PIP2] were estimated at 261 microm (95% confidence limit; 192-381 microm), rising to 693 microm (417-1153 microm) in neurons overexpressing PI5-K. Changes in membrane [PIP2] during application of oxotremorine-M were calculated from fluorescence data. The results, taken in conjunction with previous data for KCNQ2/3 (Kv7.2/Kv7.3) channel gating by PIP2 (Zhang et al., 2003), accorded with the hypothesis that the inhibitory action of oxotremorine-M on M current resulted from depletion of PIP2. The effects of bradykinin require additional components of action, which might involve IP3-induced Ca2+ release and consequent M-channel inhibition (as proposed previously) and stimulation of PIP2 synthesis by Ca2+-dependent activation of NCS-1.
    MeSH term(s) Animals ; Animals, Newborn ; Bradykinin/pharmacology ; Calcium/metabolism ; Calcium-Binding Proteins/metabolism ; Cell Membrane/drug effects ; Cell Membrane/physiology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Interactions ; Electric Stimulation/methods ; Estrenes/pharmacology ; Female ; Fluorescent Dyes/metabolism ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism ; Gene Expression/physiology ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Immunohistochemistry/methods ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Male ; Microscopy, Confocal/methods ; Muscarinic Agonists/pharmacology ; Mutation/physiology ; Neural Inhibition/drug effects ; Neural Inhibition/physiology ; Neuronal Calcium-Sensor Proteins ; Neurons/cytology ; Neurons/drug effects ; Neurons/physiology ; Neuropeptides/metabolism ; Oxotremorine/analogs & derivatives ; Oxotremorine/pharmacology ; Patch-Clamp Techniques/methods ; Phosphatidylinositol 4,5-Diphosphate/physiology ; Phosphodiesterase Inhibitors/pharmacology ; Phospholipase C delta ; Pyrrolidinones/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Muscarinic/drug effects ; Receptors, Muscarinic/genetics ; Receptors, Muscarinic/metabolism ; Superior Cervical Ganglion/cytology ; Transfection/methods ; Type C Phospholipases/genetics ; Type C Phospholipases/metabolism
    Chemical Substances Calcium-Binding Proteins ; Estrenes ; Fluorescent Dyes ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; Isoenzymes ; Muscarinic Agonists ; Neuronal Calcium-Sensor Proteins ; Neuropeptides ; Phosphatidylinositol 4,5-Diphosphate ; Phosphodiesterase Inhibitors ; Pyrrolidinones ; Receptors, Muscarinic ; frequenin calcium sensor proteins ; 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (112648-68-7) ; Green Fluorescent Proteins (147336-22-9) ; Oxotremorine (5RY0UWH1JL) ; oxotremorine M (63939-65-1) ; Type C Phospholipases (EC 3.1.4.-) ; Phospholipase C delta (EC 3.1.4.11) ; Bradykinin (S8TIM42R2W) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2006-01-13
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.3231-04.2005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Activation and inhibition of neuronal G protein-gated inwardly rectifying K(+) channels by P2Y nucleotide receptors.

    Filippov, Alexander K / Fernández-Fernández, Jose M / Marsh, Stephen J / Simon, Joseph / Barnard, Eric A / Brown, David A

    Molecular pharmacology

    2004  Volume 66, Issue 3, Page(s) 468–477

    Abstract: Neuronal signaling by G protein-coupled P2Y nucleotide receptors is not well characterized. We studied here the coupling of different molecularly defined P2Y receptors to neuronal G protein-gated inward rectifier K(+) (GIRK) channels. Individual P2Y ... ...

    Abstract Neuronal signaling by G protein-coupled P2Y nucleotide receptors is not well characterized. We studied here the coupling of different molecularly defined P2Y receptors to neuronal G protein-gated inward rectifier K(+) (GIRK) channels. Individual P2Y receptors were coexpressed with GIRK1+GIRK2 (Kir3.1 + 3.2) channels by intranuclear plasmid injections into cultured rat sympathetic neurons. Currents were recorded using perforated-patch or whole-cell (disrupted patch) techniques, with similar results. P2Y(1) receptor stimulation with 2-methylthio ADP (2-MeSADP) induced activation of GIRK current (I(GIRK)) followed by inhibition. In contrast, stimulation of endogenous alpha(2)-adrenoceptors by norepinephrine produced stable activation without inhibition. P2Y(1)-mediated inhibition was also seen when 2-MeSADP was applied after I(GIRK) preactivation by norepinephrine or by expression of Gbeta(1)gamma(2) subunits. In contrast, stimulation of P2Y(4) receptors with UTP or P2Y(6) receptors with UDP produced very little I(GIRK) activation but significantly inhibited preactivated currents. Current activation was prevented by pertussis toxin (PTX) or after coexpression of the betagamma-scavenger transducin-Galpha.I(GIRK) inhibition by all three nucleotide receptors was insensitive to PTX and was significantly reduced after coexpression of RGS2 protein, known to inhibit G(q)alpha signaling. Inhibition was not affected 1) after coexpression of RGS11, which interferes with G(q)betagamma action; 2) after coexpression of phospholipase C (PLC) delta-Pleckstrin homology domain, which sequesters the membrane phospholipid phosphatidylinositol 4,5-bisphosphate; (3) after buffering intracellular Ca(2+) with 1,2-bis(2-aminiphenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM); and (4) after pretreatment with the protein kinase C inhibitor 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF 109203X). We conclude that activation of I(GIRK) by P2Y receptors is mediated by G(i/o)betagamma, whereas I(GIRK) inhibition is mediated by G(q)alpha. These effects may provide a mechanism for P2Y-modulation of neuronal excitability.
    MeSH term(s) Animals ; Calcium/metabolism ; Cells, Cultured ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; GTP-Binding Proteins/metabolism ; Male ; Neurons/metabolism ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; Potassium Channels/metabolism ; Potassium Channels, Inwardly Rectifying ; Protein Kinase C/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Purinergic P2/physiology ; Receptors, Purinergic P2Y1 ; Type C Phospholipases/metabolism
    Chemical Substances G Protein-Coupled Inwardly-Rectifying Potassium Channels ; P2ry1 protein, rat ; Phosphatidylinositol 4,5-Diphosphate ; Potassium Channels ; Potassium Channels, Inwardly Rectifying ; Receptors, Purinergic P2 ; Receptors, Purinergic P2Y1 ; purinoceptor P2Y4 ; purinoceptor P2Y6 ; Protein Kinase C (EC 2.7.11.13) ; Type C Phospholipases (EC 3.1.4.-) ; GTP-Binding Proteins (EC 3.6.1.-) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2004-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 124034-1
    ISSN 1521-0111 ; 0026-895X
    ISSN (online) 1521-0111
    ISSN 0026-895X
    DOI 10.1124/mol.66.3.
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  7. Article: Characterization and channel coupling of the P2Y(12) nucleotide receptor of brain capillary endothelial cells.

    Simon, Joseph / Filippov, Alexander K / Göransson, Sara / Wong, Yung H / Frelin, Christian / Michel, Anton D / Brown, David A / Barnard, Eric A

    The Journal of biological chemistry

    2002  Volume 277, Issue 35, Page(s) 31390–31400

    Abstract: Rat brain capillary endothelial (B10) cells express an unidentified nucleotide receptor linked to adenylyl cyclase inhibition. We show that this receptor in B10 cells is identical in sequence to the P2Y(12) ADP receptor ("P2Y(T)") of platelets. When ... ...

    Abstract Rat brain capillary endothelial (B10) cells express an unidentified nucleotide receptor linked to adenylyl cyclase inhibition. We show that this receptor in B10 cells is identical in sequence to the P2Y(12) ADP receptor ("P2Y(T)") of platelets. When expressed heterologously, 2-methylthio-ADP (2-MeSADP; EC(50), 2 nm), ADP, and adenosine 5'-O-(2-thio)diphosphate were agonists of cAMP decrease, and 2-propylthio-D-beta,gamma-difluoromethylene-ATP was a competitive antagonist (K(B), 28 nm), as in platelets. However, 2-methylthio-ATP (2-MeSATP) (EC(50), 0.4 nm), ATP (1.9 microm), and 2-chloro-ATP (190 nm), antagonists in the platelet, were also agonists. 2-MeSADP activated (EC(50), 0.1 nm) GIRK1/GIRK2 inward rectifier K(+) channels when co-expressed with P2Y(12) receptors in sympathetic neurons. Surprisingly, P2Y(1) receptors expressed likewise gave that response; however, a full inactivation followed, absent with P2Y(12) receptors. A new P2Y(12)-mediated transduction was found, the closing of native N-type Ca(2+) channels; again both 2-MeSATP and 2-MeSADP are agonists (EC(50), 0.04 and 0.1 nm, respectively). That action, like their cAMP response, was pertussis toxin-sensitive. The Ca(2+) channel inhibition and K(+) channel activation are mediated by beta gamma subunit release from a heterotrimeric G-protein. G alpha subunit types in B10 cells were also identified. The presence in the brain capillary endothelial cell of the P2Y(12) receptor is a significant extension of its functional range.
    MeSH term(s) Adenylate Cyclase Toxin ; Adenylyl Cyclases/metabolism ; Amino Acid Sequence ; Animals ; Astrocytoma ; Binding, Competitive ; Brain Neoplasms ; CHO Cells ; Capillaries/physiology ; Cerebrovascular Circulation/physiology ; Cloning, Molecular ; Cricetinae ; Endothelium, Vascular/physiology ; GTP-Binding Proteins/metabolism ; Humans ; Ion Channels/physiology ; Kinetics ; Membrane Proteins ; Molecular Sequence Data ; Pertussis Toxin ; Plasmids ; Rats ; Receptor Cross-Talk/physiology ; Receptors, Purinergic P2/chemistry ; Receptors, Purinergic P2/drug effects ; Receptors, Purinergic P2/genetics ; Receptors, Purinergic P2/physiology ; Receptors, Purinergic P2Y12 ; Recombinant Proteins/chemistry ; Recombinant Proteins/metabolism ; Sequence Alignment ; Sequence Homology, Amino Acid ; Transfection ; Tumor Cells, Cultured ; Virulence Factors, Bordetella/pharmacology
    Chemical Substances Adenylate Cyclase Toxin ; Ion Channels ; Membrane Proteins ; P2RY12 protein, human ; P2ry12 protein, rat ; Receptors, Purinergic P2 ; Receptors, Purinergic P2Y12 ; Recombinant Proteins ; Virulence Factors, Bordetella ; Pertussis Toxin (EC 2.4.2.31) ; GTP-Binding Proteins (EC 3.6.1.-) ; Adenylyl Cyclases (EC 4.6.1.1)
    Language English
    Publishing date 2002-06-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M110714200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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