T. Kendall Harden
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View article: Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations
Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations Open
Direct activation of the human phospholipase C-γ isozymes (PLC-γ1, -γ2) by tyrosine phosphorylation is fundamental to the control of diverse biological processes, including chemotaxis, platelet aggregation, and adaptive immunity. In turn, …
View article: Agonist-induced desensitization of a P2Y-purinergic receptor-regulated phospholipase C.
Agonist-induced desensitization of a P2Y-purinergic receptor-regulated phospholipase C. Open
A guanine nucleotide-dependent P2Y-purinergic receptor-regulated phospholipase C activity of turkey erythrocyte membranes has been characterized in detail previously (Boyer, J. L., Downes, C. P., and Harden, T. K. (1989) J. Biol. Chem. 264…
View article: Differential Regulation of the Uridine Nucleotide-activated P2Y4 and P2Y6 Receptors: SER-333 AND SER-334 IN THE CARBOXYL TERMINUS ARE INVOLVED IN AGONIST-DEPENDENT PHOSPHORYLATION DESENSITIZATION AND INTERNALIZATION OF THE P2Y4 RECEPTOR
Differential Regulation of the Uridine Nucleotide-activated P2Y4 and P2Y6 Receptors: SER-333 AND SER-334 IN THE CARBOXYL TERMINUS ARE INVOLVED IN AGONIST-DEPENDENT PHOSPHORYLATION DESENSITIZATION AND INTERNALIZATION OF THE P2Y4 RECEPTOR Open
Agonist-promoted regulation of the uridine nucleotide-activated human P2Y4 receptor (P2Y4-R) and P2Y6 receptor (P2Y6-R) was studied. Incubation of P2Y4-R-expressing 1321N1 human astrocytoma cells with the cognate agonist UTP resulted in ra…
View article: Beta gamma-subunit activation of G-protein-regulated phospholipase C
Beta gamma-subunit activation of G-protein-regulated phospholipase C Open
The availability of purified G alpha 11 and the G-protein-regulated phospholipase C from turkey erythrocytes has allowed an examination of the direct effects of G-protein beta gamma-subunit on the components of the inositol lipid signaling…
View article: Role of Isoprenoid Lipids on the Heterotrimeric G Protein γ Subunit in Determining Effector Activation
Role of Isoprenoid Lipids on the Heterotrimeric G Protein γ Subunit in Determining Effector Activation Open
Post-translational prenylation of heterotrimeric G protein gamma subunits is essential for high affinity alpha-beta gamma and alpha-beta gamma-receptor interactions, suggesting that the prenyl group is an important domain in the beta gamma…
View article: Identification of an Ecto-nucleoside Diphosphokinase and Its Contribution to Interconversion of P2 Receptor Agonists
Identification of an Ecto-nucleoside Diphosphokinase and Its Contribution to Interconversion of P2 Receptor Agonists Open
The P2Y4 receptor is selectively activated by UTP. Although addition of neither ATP nor UDP alone increased intracellular Ca2+ in 1321N1 human astrocytoma cells stably expressing the P2Y4 receptor, combined addition of these nucleotides re…
View article: Protein Kinase C Phosphorylates RGS2 and Modulates Its Capacity for Negative Regulation of Gα 11 Signaling
Protein Kinase C Phosphorylates RGS2 and Modulates Its Capacity for Negative Regulation of Gα 11 Signaling Open
RGS proteins (regulators of G protein signaling) attenuate heterotrimeric G protein signaling by functioning as both GTPase-activating proteins (GAPs) and inhibitors of G protein/effector interaction. RGS2 has been shown to regulate Galpha…
View article: Purification of an AlF4- and G-protein beta gamma-subunit-regulated phospholipase C-activating protein.
Purification of an AlF4- and G-protein beta gamma-subunit-regulated phospholipase C-activating protein. Open
A 150-kDa phospholipase C has previously been purified from turkey erythrocytes and has been shown by reconstitution with turkey erythrocyte membranes to be a receptor- and G-protein-regulated enzyme (Morris, A. J., Waldo, G. L., Downes, C…
View article: A Guanine Nucleotide-independent Inwardly Rectifying Cation Permeability Is Associated with P2Y 1 Receptor Expression in Xenopus Oocytes
A Guanine Nucleotide-independent Inwardly Rectifying Cation Permeability Is Associated with P2Y 1 Receptor Expression in Xenopus Oocytes Open
The functional properties of the G protein-coupled P2Y1 receptor were investigated in Xenopus oocytes. Incubation of oocytes expressing either the human or turkey P2Y1 receptor with adenine nucleotide agonists resulted in an increase in Cl…
View article: Direct Demonstration of Mechanically Induced Release of Cellular UTP and Its Implication for Uridine Nucleotide Receptor Activation
Direct Demonstration of Mechanically Induced Release of Cellular UTP and Its Implication for Uridine Nucleotide Receptor Activation Open
ATP is released from most cell types and functions as an extracellular signaling molecule through activation of members of the two large families of P2X and P2Y receptors. Although three mammalian P2Y receptors have been cloned that are se…
View article: Activation of Phospholipase C-ε by Heterotrimeric G Protein βγ-Subunits
Activation of Phospholipase C-ε by Heterotrimeric G Protein βγ-Subunits Open
PLC-epsilon was identified recently as a phosphoinositide-hydrolyzing phospholipase C (PLC) containing catalytic domains (X, Y, and C2) common to all PLC isozymes as well as unique CDC25- and Ras-associating domains. Novel regulation of th…
View article: A receptor and G-protein-regulated polyphosphoinositide-specific phospholipase C from turkey erythrocytes. I. Purification and properties.
A receptor and G-protein-regulated polyphosphoinositide-specific phospholipase C from turkey erythrocytes. I. Purification and properties. Open
Eighty-three percent of polyphosphoinositide-specific phospholipase C activity was recovered in a cytosolic fraction after nitrogen cavitation of turkey erythrocytes. This activity has been purified approximately 50,000-fold when compared …
View article: Dominant-negative Inhibition of Pheromone Receptor Signaling by a Single Point Mutation in the G Protein α Subunit
Dominant-negative Inhibition of Pheromone Receptor Signaling by a Single Point Mutation in the G Protein α Subunit Open
In yeast, two different constitutive mutants of the G protein alpha subunit have been reported. Gpa1(Q323L) cannot hydrolyze GTP and permanently activates the pheromone response pathway. Gpa1(N388D) was also proposed to lack GTPase activit…
View article: A receptor and G-protein-regulated polyphosphoinositide-specific phospholipase C from turkey erythrocytes. II. P2Y-purinergic receptor and G-protein-mediated regulation of the purified enzyme reconstituted with turkey erythrocyte ghosts.
A receptor and G-protein-regulated polyphosphoinositide-specific phospholipase C from turkey erythrocytes. II. P2Y-purinergic receptor and G-protein-mediated regulation of the purified enzyme reconstituted with turkey erythrocyte ghosts. Open
The preceding paper describes purification and properties of a 150-kDa polyphosphoinositide-specific phospholipase C from a cytosolic fraction of turkey erythrocytes (Morris, A. J., Waldo, G. L., Downes, C. P., and Harden, T. K. (1990) J. …
View article: RGS6, RGS7, RGS9, and RGS11 Stimulate GTPase Activity of G i Family G-proteins with Differential Selectivity and Maximal Activity
RGS6, RGS7, RGS9, and RGS11 Stimulate GTPase Activity of G i Family G-proteins with Differential Selectivity and Maximal Activity Open
Regulator of G-protein signaling (RGS) proteins are GTPase activating proteins (GAPs) of heterotrimeric G-proteins that alter the amplitude and kinetics of receptor-promoted signaling. In this study we defined the G-protein alpha-subunit s…
View article: Selective activation of phospholipase C by recombinant G-protein alpha- and beta gamma-subunits.
Selective activation of phospholipase C by recombinant G-protein alpha- and beta gamma-subunits. Open
Receptor activation of phospholipase C (PLC) via G-proteins occurs by pertussis toxin-sensitive and toxin-insensitive signaling pathways. The alpha-subunits of the Gq family are presumed to mediate the toxin-insensitive pathway, but the na…
View article: Gβ Association and Effector Interaction Selectivities of the Divergent Gγ Subunit Gγ 13
Gβ Association and Effector Interaction Selectivities of the Divergent Gγ Subunit Gγ 13 Open
G gamma(13) is a divergent member of the G gamma subunit family considered to be a component of the gustducin G-protein heterotrimer involved in bitter and sweet taste reception in taste bud cells. G gamma(13) contains a C-terminal asparag…
View article: Constitutive Release of ATP and Evidence for Major Contribution of Ecto-nucleotide Pyrophosphatase and Nucleoside Diphosphokinase to Extracellular Nucleotide Concentrations
Constitutive Release of ATP and Evidence for Major Contribution of Ecto-nucleotide Pyrophosphatase and Nucleoside Diphosphokinase to Extracellular Nucleotide Concentrations Open
Nucleotides are important extracellular signaling molecules. At least five mammalian P2Y receptors exist that are specifically activated by ATP, UTP, ADP, or UDP. Although the existence of ectoenzymes that metabolize extracellular nucleoti…
View article: Combination of immunocytochemistry and radioligand receptor assay to identify beta-adrenergic receptor subtypes on astroglia in vitro
Combination of immunocytochemistry and radioligand receptor assay to identify beta-adrenergic receptor subtypes on astroglia in vitro Open
There is an increasing need to assess the distribution of receptors for neuroactive substances on specific neural cell types. This study describes the establishment of methodology that combines the quantification of beta-adrenergic recepto…
View article: RhoA Activates Purified Phospholipase C-ϵ by a Guanine Nucleotide-dependent Mechanism
RhoA Activates Purified Phospholipase C-ϵ by a Guanine Nucleotide-dependent Mechanism Open
Phospholipase C-epsilon (PLC-epsilon) is a recently identified PLC isoform activated by subunits of heterotrimeric G proteins (Galpha(12), Galpha(13), and Gbetagamma) as well as by the low molecular weight GTPases, Rho and Ras. To define t…
View article: Purification and G Protein Subunit Regulation of a Phospholipase C-β from Xenopus laevis Oocytes
Purification and G Protein Subunit Regulation of a Phospholipase C-β from Xenopus laevis Oocytes Open
Xenopus oocytes exhibit both pertussis toxin-sensitive and -insensitive inositol lipid signaling responses to G protein-coupled receptor activation. The G protein subunits Galphai, Galphao, Galphaq, Galphas, and Gbetagamma all have been pr…
View article: Requirement of Cys 399 for Processing of the Human Ecto-ATPase (NTPDase2) and Its Implications for Determination of the Activities of Splice Variants of the Enzyme
Requirement of Cys 399 for Processing of the Human Ecto-ATPase (NTPDase2) and Its Implications for Determination of the Activities of Splice Variants of the Enzyme Open
Ecto-ATPase (CD39L1) corresponds to the type 2 enzyme of the ecto-nucleoside triphosphate diphosphohydrolase family (E-NTPDase). We have isolated from human ECV304 cells three cDNAs with high homology with members of the E-NTPDase family t…
View article: Synthesis of Extended Uridine Phosphonates Derived from an Allosteric P2Y2 Receptor Ligand
Synthesis of Extended Uridine Phosphonates Derived from an Allosteric P2Y2 Receptor Ligand Open
In this study we report the synthesis of C5/C6-fused uridine phosphonates that are structurally related to earlier reported allosteric P2Y2 receptor ligands. A silyl-Hilbert-Johnson reaction of six quinazoline-2,4-(1H,3H)-dione-like base m…
View article: Charged residues in the C-terminus of the P2Y1 receptor constitute a basolateral-sorting signal
Charged residues in the C-terminus of the P2Y1 receptor constitute a basolateral-sorting signal Open
The P2Y1 receptor is localized to the basolateral membrane of polarized Madin-Darby canine kidney (MDCK) cells. In the present study, we identified a 25-residue region within the C-terminal tail (C-tail) of the P2Y1 receptor that directs b…
View article: Human P2Y 14 Receptor Agonists: Truncation of the Hexose Moiety of Uridine-5′-Diphosphoglucose and Its Replacement with Alkyl and Aryl Groups
Human P2Y 14 Receptor Agonists: Truncation of the Hexose Moiety of Uridine-5′-Diphosphoglucose and Its Replacement with Alkyl and Aryl Groups Open
Uridine-5′-diphosphoglucose (UDPG) activates the P2Y14 receptor, a neuroimmune system GPCR. P2Y14 receptor tolerates glucose substitution with small alkyl or aryl groups or its truncation to uridine-5′-diphosphate (UDP), a full agonist hum…
View article: Mechanism of Phosphorylation-induced Activation of Phospholipase C-γ Isozymes
Mechanism of Phosphorylation-induced Activation of Phospholipase C-γ Isozymes Open
The lipase activity of most phospholipases C (PLCs) is basally repressed by a highly degenerate and mostly disordered X/Y linker inserted within the catalytic domain. Release of this auto-inhibition is driven by electrostatic repulsion bet…
View article: Agonist Versus Antagonist Action of ATP at the P2Y 4 Receptor Is Determined by the Second Extracellular Loop
Agonist Versus Antagonist Action of ATP at the P2Y 4 Receptor Is Determined by the Second Extracellular Loop Open
UTP is a potent full agonist at both the human P2Y4 (hP2Y4) and rat P2Y4 (rP2Y4) receptor. In contrast, ATP is a potent full agonist at the rP2Y4 receptor but is a similarly potent competitive antagonist at the hP2Y4 receptor. To delineate…
View article: Phospholipase C isozymes as effectors of Ras superfamily GTPases
Phospholipase C isozymes as effectors of Ras superfamily GTPases Open
The physiological effects of many extracellular stimuli are initiated through receptor-promoted activation of phospholipase C and inositol lipid signaling pathways. The historical view that phospholipase C-promoted signaling primarily occu…