Biomedical subjects

Z Chen

Publications and source records attributed to Z Chen.

At least 19 recordsLinked to original sources

PubMed2025

HLA-E and NKG2A Mediate Resistance to BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) is the first-line therapy for high-grade non-muscle-invasive bladder cancer (NMIBC), yet many patients experience recurrence due to immune evasion. We identify HLA-E and NKG2A as mediators of adaptive resistance involving chronic activation of NK and T cells in BCG-unresponsive tumors. Prolonged IFN-γ exposure enhances HLA-E and PD-L1 expression on recurrent tumors, accompanied by the accumulation of NKG2A+ NK and CD8 T cells. HLA-Ehigh tumor cells preferentially cluster near CXCL12-rich stromal regions with dense effector cell presence, underscoring a spatially segregated tumor architecture. Although cytotoxic lymphocytes retain effector potential, their activity is restrained by HLA-E/NKG2A and PD-L1/PD-1 pathways located in their immediate neighborhood within the bladder tumor microenvironment. These data reveal a spatially organized immune escape program that limits anti-tumor immunity. Our findings support dually targeting NKG2A and PD-L1 checkpoint blockade as a rational, bladder-sparing strategy for patients with BCG-unresponsive NMIBC.

BCG-unresponsive↗

PubMed1995

Adapter function of protein-tyrosine phosphatase 1D in insulin receptor/insulin receptor substrate-1 interaction.

Insulin signal transduction involves the multisite docking protein insulin receptor substrate-1 (IRS-1) and a number of Src homology-2 (SH2) domain factors, including p85/p110 phosphatidylinositol 3-kinase, p110 GTPase-activating protein, and the phosphotyrosine-specific phosphatase PTP1D. In transfected baby hamster kidney cells, Rat1 fibroblasts, and normal IM9 lymphoblasts, PTP1D directly binds activated insulin receptor. This interaction is mediated by catalytic domain-proximal SH2 determinants of the phosphatase and phosphotyrosine 1146 of the activated insulin receptor. While the receptor and the phosphatase do not serve as substrates for each other, their interaction promotes IRS-1 binding to the receptor, indicating that PTP1D functions as an adapter for insulin receptor and IRS-1. The formation of a multiprotein signaling complex involving the insulin receptor, PTP1D, and IRS-1 enhances cellular glucose uptake, a critical process in the physiological action of insulin.

Amino Acid Sequence↗

PubMed1995

Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination.

The inhibitor protein I kappa B alpha controls the nuclear import of the transcription factor NF-kappa B. The inhibitory activity of I kappa B alpha is regulated from the cytoplasmic compartment by signal-induced proteolysis. Previous studies have shown that signal-dependent phosphorylation of serine residues 32 and 36 targets I kappa B alpha to the ubiquitin-proteasome pathway. Here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of I kappa B alpha. Conservative Lys-->Arg substitutions at both Lys-21 and Lys-22 produce dominant-negative mutants of I kappa B alpha in vivo. These constitutive inhibitors are appropriately phosphorylated but fail to release NF-kappa B in response to multiple inducers, including viral proteins, cytokines, and agents that mimic antigenic stimulation through the T-cell receptor. Moreover, these Lys-->Arg mutations prevent signal-dependent degradation of I kappa B alpha in vivo and ubiquitin conjugation in vitro. We conclude that site-specific ubiquitination of phosphorylated I kappa B alpha at Lys-21 and/or Lys-22 is an obligatory step in the activation of NF-kappa B.

Arginine↗

PubMed1995

Expression of type V adenylyl cyclase is required for epidermal growth factor-mediated stimulation of cAMP accumulation.

Previously, this laboratory has demonstrated that epidermal growth factor (EGF) increases adenylyl cyclase activity in cardiac membranes and elevates cAMP accumulation in hearts and cardiac myocytes. Since EGF does not increase cAMP accumulation in all tissues, we investigated the possibility that the expression of a specific isoform of adenylyl cyclase (AC) was necessary to observe EGF-elicited stimulation of cAMP accumulation. HEK 293 cells were transfected with different isoforms of AC, and the ability of EGF to increase AC activity as well as elevate cAMP accumulation was determined. In cells transfected with AC I, II, V, and VI cDNAs, neither the expression nor the amount of the two isoforms of Gs alpha (45 and 52 kDa) were altered. Similarly, EGF-elicited phosphorylation of cellular proteins on tyrosine residues in various transfectants was unaltered. However, EGF increased AC activity and elevated cAMP accumulation only in cells expressing the rat and canine ACV. EGF did not alter either AC activity or cAMP accumulation in cells overexpressing types I, II, and VI isozymes. As assessed by the ability of an anti-Gs alpha antibody to obliterate the effect, stimulation of AC activity in AC V transfectants involved the participation of Gs alpha, a finding consistent with previous data concerning EGF effects on cardiac AC (Nair, B. G., Parikh, B., Milligan, G., and Patel, T. B. (1990) J. Biol. Chem. 265, 21317-21322). Thus we conclude that the expression of AC V isoform confers specificity to the ability of EGF to stimulate AC activity.

Adenosine Triphosphate↗

PubMed1995

Effects of EMD 57033 on contraction and relaxation in isolated rabbit hearts.

BACKGROUND: Ca2+ sensitizers are reported to enhance contractility with modest effects on energy utilization. In the present study we assessed the effects of the relatively "pure" Ca2+ sensitizer EMD 57033 on mechanical performance and energy consumption in the beating heart. METHODS AND RESULTS: In 10 isolated, red blood cell-perfused rabbit hearts the effects of EMD 57033 (5.0 to 5.8 mumol/L) on left ventricular (LV) pressure and O2 consumption (VO2) were examined at heart rates of 100 and 150 beats per minute (bpm) and perfusate [Ca2+] ([Ca2+]o) of 2.5 and 1.0 mmol/L (isovolumic contractions). LV developed pressure and maximum dP/dt increased, but less so at 150 bpm or 1.0 mmol/L [Ca2+]. End-diastolic pressure also increased, more so at 150 bpm or 1.0 mmol/L [Ca2+]o. EMD 57033 decreased time to peak isovolumic pressure (Tmax) and prolonged time to 50% pressure decline (T1/2). These changes were greater at slower heart rate or lower [Ca2+]o. The magnitude of increased VO2 with EMD 57033 was greater at 100 bpm than 150 bpm but unaffected by [Ca2+]o. We then investigated the influence of ejection on the response to EMD 57033 (n = 7). The increase in developed pressure with EMD 57033 was greater for ejecting than isovolumic beats (25.5 +/- 10.2 versus 14.7 +/- 7.5 mm Hg at 100 bpm, P < .01), while the increase in end-diastolic pressure was less (P = NS). The increase in VO2 was significantly greater for ejecting than isovolumic beats (0.027 +/- 0.013 versus 0.020 +/- 0.009 mL O2/beat per 100 g at 100 bpm, P < .01). CONCLUSIONS: EMD 57033 enhances contractility and prolongs relaxation. Its effects are modulated by heart rate, [Ca2+]o, and contraction mode, with positive inotropic effects being more prominent for ejecting beats.

Animals↗

PubMed1995

Increase in suprabasilar integrin adhesion molecule expression in human epidermal neoplasms accompanies increased proliferation occurring with immortalization and tumor progression.

In a previous prospective study of 80 patients with squamous cell carcinoma of the upper aerodigestive tract, a progressive increase in expression of the integrin cell adhesion molecule alpha 6 beta 4 in suprabasilar cell layers of the tumor parenchyma was associated with an increase in early recurrence after therapy. In this study, we determined the relationship of the altered expression pattern of the integrin to changes occurring during benign, invasive, or metastatic stages of tumor development. Suprabasilar expression of integrin alpha 6 beta 4 appeared with neoplastic transformation in benign squamous papillomas, but homogeneous expression occurred more frequently in the parenchyma of primary and metastatic squamous cell carcinomas. The variation in the extent of suprabasilar integrin expression among the tumors corresponded to the variation in the population undergoing proliferation as determined by two independent markers of proliferation. Integrin expression was quantified in primary, HPV 16 DNA-immortalized, and v-ki-ras oncogene-transformed keratinocytes, and the pattern of expression was compared with cell cycle progression. Primary keratinocyte lines showed a bimodal distribution of integrin expression, with one population showing decreased integrin expression, cell size, and a block of cell cycle progression consistent with differentiation, whereas another population exhibited high integrin expression and full progression through the cell cycle, consistent with proliferation. HPV-immortalized and v-ki-ras-transformed cell lines undergoing continuous proliferation exhibited uniformly strong integrin expression, which was similar in intensity to that observed in the proliferating population of normal keratinocytes. Similar increases in expression of two additional integrins, alpha 2 beta 1 and alpha 3 beta 1, occurred along with integrin alpha 6 beta 4 in tissue specimens and cell lines derived from neoplasms. Thus, epidermal neoplasms display an increase in a population of cells exhibiting constitutive expression of a repertoire of integrins, which is similar to that found transiently in the acute phase of epidermal wound healing, a physiological response in which hyperproliferation, retention of multiple layers of proliferating cells, and migration occur. The association of a progressive increase in suprabasilar expression of these integrins with early tumor recurrence and advanced neoplasia suggests that constitutive expression and function of the same repertoire of integrins may be advantageous, rather than sufficient, for tumor progression.

Antigens, Surface↗

PubMed1995

Unitary anion currents through phospholemman channel molecules.

Phospholemman (PLM) is a 72-amino-acid peptide with a single transmembrane domain, the expression of which induces chloride currents in Xenopus oocytes. It has remained unknown whether PLM is an ion channel or acts as a channel regulator. Here we show, by measuring unitary anion currents across planar phospholipid bilayers to which immunoaffinity-purified recombinant PLM was added, that it does indeed form ion channels. Excised patches of oocytes expressing PLM had similar currents. Of the ions tested, the sulphonic amino acid taurine was the most permeant, and expression of PLM increased fluxes of radiolabelled taurine in oocytes. Phospholemman is the smallest protein in cell membranes known to form an ion channel and the taurine selectivity suggests that it is involved in cell volume regulation.

Animals↗

PubMed1995

Identification of residues in the aromatic substrate binding site of horseradish peroxidase by 1H NMR studies on isozymes.

The cyanide-inhibited complexes of two horseradish peroxidase acidic isozymes, A1 (HRPA1, unsequenced) and A2 (HRPA2, sequenced), have been examined by solution two-dimensional 1H NMR methods, and the active site molecular and electronic structure compared to that of the well-characterized isozyme C (HRPC) (Chen, Z., de Ropp, J.S., Hernández, G., & La Mar, G.N. (1994) J. Am. Chem. Soc. 116, 8772-8783), as well as to that of cytochrome c peroxidase. The identity and alignment of catalytically relevant residues near the active site for HRPA1-CN and HRPA2-CN are determined, and key residue replacements implicated in the differential catalytic properties of the acidic vs C isozymes are identified. Heme and axial His contact shift patterns, as well as dipolar contacts of residues with the heme and with each other, confirm a highly conserved structure among the three isozymes, including for the distal pocket residues involved in the activation of the enzyme. The remarkable dynamic stability of the heme pocket, as reflected in NH exchange with solvent, is also conserved for the three isozymes. An additional heme contact, Ile 148, is identified in HRPC-CN. Four residues in contact with the heme in HRPC-CN are replaced in HRPA2-CN, two of which are likely functionally neutral, Gly 169-->Ala and Ile 148-->Leu. However, two substitutions in the acidic isozymes in the aromatic substrate binding pocket on the heme edge, Ile 244-->Leu and Phe 179 or 221-->aliphatic residue, could well account for the dramatic decrease (approximately 10(3) in aromatic substrate binding in the A1 and A2 isozymes vs the C isozyme of HRP.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1995

Role of reactive nitrogen intermediates in the regulation of allogeneic skin graft survival in mice after portal vein pretransplant transfusion.

C3H/HeJ mice received multiple minor histoincompatible skin grafts (B10.BR) after portal or lateral tail vein injection of irradiated B10.BR spleen cells. Some mice were additionally injected with a competitive inhibitor of nitric oxide synthesis (NG-monomethyl-L-arginine [NMMA]). Skin graft survival was extended following portal venous immunization, and further enhanced by NMMA. Both treatments produced decreased production of nitrate/nitrite in vivo, and were associated with enhanced expression of mRNA in vivo for type 2 cytokines (interleukins 4 and 10), as well as increased synthesis of the latter on restimulation in vitro. Inducible nitric oxide synthase gene expression was up-regulated both in the local mucosal immune system (intraepithelial lymphocytes) and systemically (spleen) following antigen challenge by the portal vein or by gavage, with or without additional NMMA treatment. In contrast, when we studied a possible alternate in vivo source of nitric oxide production, we found that endothelial cell nitric oxide synthase expression was reproducibly up-regulated only in splenic tissue after combined oral (or portal) immunization and NMMA, and was not up-regulated in tissues local to the site of injection (intraepithelial lymphocytes).

Animals↗

PubMed1995

Kinetic studies of isopeptidase T: modulation of peptidase activity by ubiquitin.

We have investigated the specificity of isopeptidase T toward peptide-AMC substrates based on the C-termini of ubiquitin. The substrates investigated were Z-Gly-Gly-AMC, Z-Arg-Gly-Gly-AMC, Z-Leu-Arg-Gly-Gly-AMC, and Z-Arg-Leu-Arg-Gly-Gly-AMC and were hydrolyzed by isopeptidase T with kc/Km values of < 0.1, 1, 18, and 95 M-1 s-1, respectively. In the course of these experiments, we observed that the hydrolytic activity of isopeptidase T toward these substrates is modulated by ubiquitin in a biphasic fashion. While submicromolar concentrations of ubiquitin activate isopeptidase T, higher concentrations are inhibitory. In the activation phase, the extent of stimulation of kc/Km varies with substrate and is 8-, 50-, and 70-fold for Z-Arg-Gly-Gly-AMC, Z-Leu-Arg-Gly-Gly-AMC, and Z-Arg-Leu-Arg-Gly-Gly-AMC, respectively. Kd for ubiquitin in this phase is, of course, independent of substrate and equals 0.10 +/- 0.03 microM. At higher concentrations, ubiquitin is inhibitory and titrates kc/Km with an average Ki value of 3.0 +/- 1.3 microM for all three substrates. To explain these observations, we propose a structural model for isopeptidase T that involves two binding sites for ubiquitin. We propose that the two sites are adjacent to one another and are the extended active site that binds two ubiquitin moieties of a polyubiquitin chain for isopeptide bond hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1995

Three-dimensional structure of a mutant HIV-1 protease displaying cross-resistance to all protease inhibitors in clinical trials.

Analysis of mutational effects in the human immunodeficiency virus type-1 (HIV-1) provirus has revealed that as few as four amino acid side-chain substitutions in the HIV-1 protease (M46I/L63P/V82T/I84V) suffice to yield viral variants cross-resistant to a panel of protease inhibitors either in or being considered for clinical trials (Condra, J. H., Schleif, W. A., Blahy, O. M., Gadryelski, L. J., Graham, D. J., Quintero, J. C., Rhodes, A., Robbins, H. L., Roth, E., Shivaprakash, M., Titus, D., Yang, T., Teppler, H., Squires, K. E., Deutsch, P. J., and Emini, E. A. (1995) Nature 374, 569-571). As an initial effort toward elucidation of the molecular mechanism of drug resistance in AIDS therapies, the three-dimensional structure of the HIV-1 protease mutant containing the four substitutions has been determined to 2.4-A resolution with an R factor of 17.1%. The structure of its complex with MK639, a protease inhibitor of the hydroxyaminopentane amide class of peptidomimetics currently in Phase III clinical trials, has been resolved at 2.0 A with an R factor of 17.0%. These structures are compared with those of the wild-type enzyme and its complex with MK639 (Chen, Z., Li, Y., Chen, E., Hall, D. L., Darke, P. L., Culberson, C., Shafer, J., and Kuo, L. C. (1994) J. Biol. Chem. 269, 26344-26348). There is no gross structural alteration of the protease due to the site-specific mutations. The C alpha tracings of the two native structures are identical with a root-mean-square deviation of 0.5 A, and the four substituted side chains are clearly revealed in the electron density map. In the MK639-bound form, the V82T substitution introduces an unfavorable hydrophilic moiety for binding in the active site and the I84V substitution creates a cavity (unoccupied by water) that should lead to a decrease in van der Waals contacts with the inhibitor. These changes are consistent with the observed 70-fold increase in the Ki value (approximately 2.5 kcal/mol) for MK639 as a result of the mutations in the HIV-1 protease. The role of the M46I and L63P substitutions in drug resistance is not obvious from the crystallographic data, but they induce conformational perturbations (0.9-1.1 A) in the flap domain of the native enzyme and may affect the stability and/or activity of the enzyme unrelated directly to binding.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Crystal structure of human alpha-thrombin complexed with hirugen and p-amidinophenylpyruvate at 1.6 A resolution.

Crystals of human alpha-thrombin complexed with hirugen and the alpha-keto acid thrombin inhibitor APPA (p-amidinophenylpyruvate) that diffract to 1.6 A resolution were obtained by soaking an alpha-thrombin-hirugen crystal in a solution of APPA. The crystal structure was determined using the difference Fourier method and refined to an R factor of 18.7% at 1.6 A resolution. This structure is the highest resolution structure of the thrombin molecule that is currently available. With the exception of the region near Arg77A-Asn78, the structures of the thrombin and hirugen molecules in the ternary complex are similar to those reported for the thrombin-hirugen binary complex. As previously determined for the APPA-trypsin complex, the carbonyl carbon atom of APPA forms a covalent bond with O gamma of Ser195 of thrombin to yield a "transition-state" analog of the tetrahedral intermediate. Comparison of the specificity pocket of the APPA complexes of thrombin and trypsin reveals differences in hydrogen bonding and shows for the first time that the S1 site of thrombin is larger than that of trypsin and as a result thrombin may be able to accommodate a bulkier P1 group than trypsin.

Amino Acid Sequence↗

PubMed1995

Demonstration that mammalian methionine synthases are predominantly cobalamin-loaded.

Methionine synthase is an important cellular housekeeping enzyme and is dependent on the cofactor cobalamin, a derivative of vitamin B12, for activity. It functions in two major metabolic pathways including the tetrahydrofolate-dependent one-carbon cycle and the salvage pathway for methionine. Its dysfunction has several physiological ramifications and leads to the development of megaloblastic anemia. In addition, it is suspected to be involved in the pathogenesis of neural tube defects. An issue that is central in weighing therapeutic options for methionine synthase-related disorders is the extent to which the enzyme exists as apoenzyme in vivo and, thus, can be potentially responsive to vitamin B12 therapy. despite the importance of this issue, the extent of holo- versus apoenzyme in mammalian tissue is controversial and unresolved. To address this question, we have developed a convenient anaerobic assay that employs titanium citrate to deliver low potential electron equivalents. The reductive activation of this enzyme is essential under in vitro assay conditions. We find that both the human placental and porcine liver methionine synthases exist predominantly in the holoenzyme form (90-100%) in the crude homogenate. In addition, the activity of the pure enzyme measured in the titanium citrate assay is also independent of exogenous cofactor, revealing that the cobalamin is tightly bound to the active site.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed1995

A subunit interaction in chloroplast ATP synthase determined by genetic complementation between chloroplast and bacterial ATP synthase genes.

F1F0-ATP synthases utilize protein conformational changes induced by a transmembrane proton gradient to synthesize ATP. The allosteric cooperativity of these multisubunit enzymes presumably requires numerous protein-protein interactions within the enzyme complex. To correlate known in vitro changes in subunit structure with in vivo allosteric interactions, we introduced the beta subunit of spinach chloroplast coupling factor 1 ATP into a bacterial F1 ATP synthase. A cloned atpB gene, encoding the complete chloroplast beta subunit, complemented a chromosomal deletion of the cognate uncD gene in Escherichia coli and was incorporated into a functional hybrid F1 ATP synthase. The cysteine residue at position 63 in chloroplast beta is known to be located at the interface between alpha and beta subunits and to be conformationally coupled, in vitro, to the nucleotide binding site > 40 A away. Enlarging the side chain of chloroplast coupling factor 1 beta residue 63 from Cys to Trp blocked ATP synthesis in vivo without significantly impairing ATPase activity or ADP binding in vitro. The in vivo coupling of nucleotide binding at catalytic sites to transmembrane proton movement may thus involve an interaction, via conformational changes, between the amino-terminal domains of the alpha and beta subunits.

Adenosine Triphosphate↗

PubMed1995

Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway.

The transcription factor NF-kappa B is sequestered in the cytoplasm by the inhibitor protein I kappa B alpha. Extracellular inducers of NF-kappa B activate signal transduction pathways that result in the phosphorylation and subsequent degradation of I kappa B alpha. At present, the link between phosphorylation of I kappa B alpha and its degradation is not understood. In this report we provide evidence that phosphorylation of serine residues 32 and 36 of I kappa B alpha targets the protein to the ubiquitin-proteasome pathway. I kappa B alpha is ubiquitinated in vivo and in vitro following phosphorylation, and mutations that abolish phosphorylation and degradation of I kappa B alpha in vivo prevent ubiquitination in vitro. Ubiquitinated I kappa B alpha remains associated with NF-kappa B, and the bound I kappa B alpha is degraded by the 26S proteasome. Thus, ubiquitination provides a mechanistic link between phosphorylation and degradation of I kappa B alpha.

Cysteine Endopeptidases↗

PubMed1995

Sequence of the genome of lactate dehydrogenase-elevating virus: heterogenicity between strains P and C.

The complete nucleotide sequence of genomic RNA (14104 nt) of one strain of lactate dehydrogenase-elevating virus (LDV), LDV-P, is reported. It exhibits only about 80% nucleotide identity with the sequence reported for another LDV strain, LDV-C (Godeny et al., Virology 194, 585-596 (1993), and is 68 nucleotides shorter than the reported LDV-C sequence. The difference in length is largely due to the lack of a 59-nucleotide-long direct repeat in ORF 1a of the reported LDV-C sequence. Sequence analysis of a total of 1.4 kb of ORF 1a of LDV-C via reverse transcription/polymerase chain reaction (RT/PCR) technology failed to confirm the presence of this repeat in the LDV-C genome as well as of 24 deletions/insertions of single nucleotides that give rise to apparent transient reading frame differences between the LDV-P and LDV-C genomes and might have represented frameshift mutations. An additional 35 nucleotides in ORF 1a of the RT/PCR LDV-C products were the same as in the LDV-P rather than the reported LDV-C genome. The nucleotide sequences of the 5' leader and the 3' noncoding ends of the two genomes and the heptanucleotides involved in joining the 5' leader to the bodies of the subgenomic mRNAs were highly conserved or identical. The predicted LDV-P proteins, however, differed from those predicted for the LDV-C proteins between 25% for the ORF 2 protein and 1% for the ORF 7 nucleocapsid protein. All functional motifs of the ORF 1a and ORF 1b proteins were conserved. The ORF 1a protein possesses 11 potential transmembrane segments that flank the serine protease domain.

Amino Acid Sequence↗

PubMed1995

Cloning, sequencing and analysis of a gene encoding Escherichia coli proline dehydrogenase.

Using a genomic subtraction technique, we cloned a DNA sequence that is present in wild-type Escherichia coli strain CSH4 but is missing in a presumptive proline dehydrogenase deletion mutant RM2. Experimental evidence indicated that the cloned fragment codes for proline dehydrogenase (EC 1.5.99.8) since RM2 cells transformed with a plasmid containing this sequence was able to survive on minimal medium supplemented with proline as the sole nitrogen and carbon sources. The cloned DNA fragment has an open reading frame of 3942 bp and encodes a protein of 1313 amino acids with a calculated Mr of 143,808. The deduced amino acid sequence of the E. coli proline dehydrogenase has an 84.9% homology to the previously reported Salmonella typhimurium putA gene but it is 111 amino acids longer at the C-terminal than the latter.

Amino Acid Sequence↗

PubMed1995

Activation of dopamine D1 receptors enhances long-term depression of synaptic transmission induced by low frequency stimulation in rat hippocampal CA1 neurons.

The effects of both activation and blockade of dopamine (DA) D1 receptors on long-term depression (LTD) of synaptic transmission were examined in CA1 neurons of rat hippocampal slices. Low frequency stimulation (LFS) consisting of 450 pulses at 1 Hz induced LTD (-14.3%, mean, n = 10) in the slope of the field excitatory postsynaptic potential. SKF-38393 (3-10 microM), an agonist of DA D1 receptors, significantly enhanced LFS-induced LTD (-31.1%, n = 11). SCH-23390 (2 microM), an antagonist of DA D1 receptors, blocked the induction of LTD by LFS (2.5%, n = 6). These results indicate that DA D1 receptors play an important role in the modulation of LFS-induced LTD in rat hippocampal CA1 neurons.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗