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Biomedical subjects

David A Baker

Publications and source records attributed to David A Baker.

29 records · Page 2Linked to original sources
PubMed2003

Inhibition of non-vesicular glutamate release by group III metabotropic glutamate receptors in the nucleus accumbens.

Previous in vitro studies have shown that group III metabotropic glutamate receptors (mGluRs) regulate synaptic glutamate release. The present study used microdialysis to characterize this regulation in vivo in rat nucleus accumbens. Reverse dialysis of the group III mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (L-AP4) decreased, whereas the antagonist (R,S)-alpha-methylserine-O-phosphate (MSOP) increased the extracellular level of glutamate. The decrease by L-AP4 or the increase by MSOP was antagonized by co-administration of MSOP or L-AP4, respectively. Activation of mGluR4a by (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid or mGluR6 by 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid had no effect on extracellular glutamate. (R,S)-4-Phosphonophenylglycine (PPG), another group III agonist with high affinity for mGluR4/6/8, reduced extracellular glutamate only at high concentrations capable of binding to mGluR7. The increase in extracellular glutamate by MSOP was tetrodotoxin-independent, and resistant to both the L-type and N-type Ca2+ channel blockers. L-AP4 failed to block 30 mm K+-induced vesicular glutamate release. Blockade of glutamate uptake by d,l-threo-beta-benzyloxyaspartate caused a Ca2+-independent elevation in extracellular glutamate that was reversed by L-AP4. Finally, (S)-4-carboxyphenylglycine, an inhibitor of cystine-glutamate antiporters, attenuated the L-AP4-induced reduction in extracellular glutamate. Together, these data indicate that group III mGluRs regulate in vivo extracellular glutamate in the nucleus accumbens by inhibiting non-vesicular glutamate release.

Aminobutyrates↗
PubMed2002

The origin and neuronal function of in vivo nonsynaptic glutamate.

Basal extracellular glutamate sampled in vivo is present in micromolar concentrations in the extracellular space outside the synaptic cleft, and neither the origin nor the function of this glutamate is known. This report reveals that blockade of glutamate release from the cystine-glutamate antiporter produced a significant decrease (60%) in extrasynaptic glutamate levels in the rat striatum, whereas blockade of voltage-dependent Na+ and Ca2+ channels produced relatively minimal changes (0-30%). This indicates that the primary origin of in vivo extrasynaptic glutamate in the striatum arises from nonvesicular glutamate release by the cystine-glutamate antiporter. By measuring [35S]cystine uptake, it was shown that similar to vesicular release, the activity of the cystine-glutamate antiporter is negatively regulated by group II metabotropic glutamate receptors (mGluR2/3) via a cAMP-dependent protein kinase mechanism. Extracellular glutamate derived from the antiporter was shown to regulate extracellular levels of glutamate and dopamine. Infusion of the mGluR2/3 antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate levels, and previous blockade of the antiporter prevented the APICA-induced rise in extracellular glutamate. This suggests that glutamate released from the antiporter is a source of endogenous tone on mGluR2/3. Blockade of the antiporter also produced an increase in extracellular dopamine that was reversed by infusing the mGluR2/3 agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxlylate, indicating that antiporter-derived glutamate can modulate dopamine transmission via mGluR2/3 heteroreceptors. These results suggest that nonvesicular release from the cystine-glutamate antiporter is the primary source of in vivo extracellular glutamate and that this glutamate can modulate both glutamate and dopamine transmission.

Animals↗
PubMed2002

The DIAP1 RING finger mediates ubiquitination of Dronc and is indispensable for regulating apoptosis.

Members of the Inhibitor of Apoptosis Protein (IAP) family block activation of the intrinsic cell death machinery by binding to and neutralizing the activity of pro-apoptotic caspases. In Drosophila melanogaster, the pro-apoptotic proteins Reaper (Rpr), Grim and Hid (head involution defective) all induce cell death by antagonizing the anti-apoptotic activity of Drosophila IAP1 (DIAP1), thereby liberating caspases. Here, we show that in vivo, the RING finger of DIAP1 is essential for the regulation of apoptosis induced by Rpr, Hid and Dronc. Furthermore, we show that the RING finger of DIAP1 promotes the ubiquitination of both itself and of Dronc. Disruption of the DIAP1 RING finger does not inhibit its binding to Rpr, Hid or Dronc, but completely abrogates ubiquitination of Dronc. Our data suggest that IAPs suppress apoptosis by binding to and targeting caspases for ubiquitination.

Animals↗
PubMed2002

A novel cyclic GMP-dependent protein kinase is expressed in the ring stage of the Plasmodium falciparum life cycle.

Cyclic GMP-dependent protein kinases (PKGs) are the major mediators of the cGMP signal transduction pathway and regulate a variety of physiological effects. We report here the characterization of an unusual PKG from the human malaria parasite Plasmodium falciparum (designated PfPKG). The 97.5 kDa protein contains some of the structural features of mammalian PKGs but, uniquely, contains a third predicted cGMP binding site and a degenerate fourth. Using both protein kinase activity assays and Western blotting with native P. falciparum proteins, we demonstrate here that PfPKG is expressed predominantly in the ring stage of the life cycle, suggesting a role in the development of asexual blood stage parasites. An Escherichia coli-derived recombinant protein (PfPKG2, Met115-Phe853) was purified and shown to have phosphotransferase activity in terms of both substrate phosphorylation and auto-phosphorylation. This activity was stimulated at least fivefold by 1.0 microM cyclic GMP, but was not stimulated by cAMP or by 8-pCPT-cGMP, which is a potent activator of mammalian PKGs. Several protein kinase inhibitors exhibited a range of inhibitory effects on PfPKG activity. Biochemical analysis therefore shows that PfPKG is distinct from mammalian PKGs with respect to both cyclic nucleotide analogue activation and inhibition profiles.

Amino Acid Sequence↗
PubMed2002

Modulation of group II metabotropic glutamate receptor signaling by chronic cocaine.

Repeated cocaine produces enduring neuroadaptations in glutamate transmission in the nucleus accumbens that are thought to contribute to addiction. Group II metabotropic glutamate autoreceptors (mGluR2/3) regulate glutamate release, and this study investigates whether repeated cocaine injection produces long-lasting alterations in mGluR2/3 content, phosphorylation, and physiology. Rats were administered cocaine daily for 1 week, and 3 weeks after the last injection, mGluR2/3 protein levels were altered in the accumbens and prefrontal cortex (PFC) but not in the dorsal striatum or ventral tegmental area. The level of mGluR2/3 dimer was elevated in the accumbens and PFC and the monomer was reduced in the PFC only. Furthermore, the relative Ser phosphorylation state of the monomer was elevated in both the accumbens and PFC of cocaine-pretreated subjects, whereas the dimer demonstrated negligible phosphorylation in either treatment group. These changes in mGluR2/3 level and phosphorylation state were associated with reduced mGluR2/3 agonist-induced guanosine 5'-3-O -(thio)triphosphate binding in the accumbens and PFC, but not in the dorsal striatum. Stimulation of mGluR2/3 reduces extracellular glutamate by inhibiting Ca(2+)-dependent and cystine/glutamate antiporter-mediated glutamate release. The capacity of the mGluR2/3 agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) to inhibit [(35)S]cystine uptake via cystine/glutamate antiporter in accumbens tissue slices was reduced by repeated cocaine. Also, the capacity of APDC to reduce the basal and potassium-stimulated extrasynaptic glutamate was significantly blunted in the accumbens of cocaine-pretreated subjects. Together, these data demonstrate that repeated cocaine produces an enduring reduction in mGluR2/3 function in the nucleus accumbens.

Animals↗
PubMed2002

Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens.

The regulation of extracellular glutamate in the nucleus accumbens by group II metabotropic glutamate receptors (mGluR2/3) was examined in vivo. Stimulation of mGluR2/3 with 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) or N-acetylaspartylglutamate reduced extracellular glutamate levels. Conversely, blockade of mGluR2/3 by LY143495 or (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate, an effect antagonized by the coadministration of APDC. These effects likely involve both vesicular and nonvesicular glutamate, because the increase in glutamate by APICA or the decrease by APDC was prevented by blocking N-type calcium channels and the release of glutamate after potassium-induced membrane depolarization was antagonized by APDC. In addition, blockade of the cystine-glutamate exchange, a major nonvesicular source of extracellular glutamate, by (S)-4-carboxyphenylglycine blocked the effects induced by either APDC or APICA. However, blockade of Na(+) channels by tetrodotoxin or Na(+)-dependent glutamate transporters by DL-threo-beta-benzyloxyaspartate failed to affect the alterations in extracellular glutamate by APICA or APDC, respectively. Group II mGluRs are G(i)-coupled and coperfusion with the cAMP-dependent protein kinase (PKA) activator Sp-cAMPS blocked the reduction in glutamate by APDC and the PKA inhibitor Rp-cAMPS prevented the elevation in glutamate by APICA. Taken together, these data support three conclusions: 1) group II mGluRs regulate both vesicular and nonvesicular release of glutamate in the nucleus accumbens, 2) there is tonic in vivo stimulation of mGluR2/3 by endogenous glutamate, and 3) modulation of group II mGluRs of extracellular glutamate is Ca(2+)- and PKA-dependent.

Amino Acid Transport System X-AG↗
PubMed2002

Valacyclovir in the treatment of genital herpes and herpes zoster.

Genital herpes is prevalent and sometimes debilitating. Likewise, herpes zoster ('shingles') can be painful and often disabling. The treatment of these conditions has been advanced over the past two decades by the introduction of guanosine nucleoside antivirals such as valacyclovir (Valtrex), Glaxo Wellcome), the highly bioavailable prodrug of acyclovir (Zovirax), Glaxo Wellcome). This review describes the pharmacology, pharmacokinetics, clinical efficacy and tolerability of valacyclovir and considers its clinical attributes in the context of those of the antivirals, acyclovir and famciclovir (Famvir), SmithKline Beecham). The data demonstrate that valacyclovir is more effective than placebo and as effective as other antivirals in the episodic and suppressive treatment of recurrent genital herpes. Valacyclovir is the only antiviral shown to be effective with a short (3-day) course in the episodic treatment of recurrent genital herpes, as well as with once-daily dosing for daily suppressive therapy. In herpes zoster, valacyclovir is as effective as famciclovir and more effective than either placebo or acyclovir at facilitating cutaneous healing and healing of zoster-associated pain and post-herpetic neuralgia. Valacyclovir is well tolerated, with convenient dosing frequencies for the treatment of genital herpes or herpes zoster, it also has the option for use as a short course therapy in the episodic treatment of recurrent genital herpes, all of which are important benefits in the management of these conditions.

Acyclovir↗
PubMedDate not supplied

Histologic comparison of a thermal dual-etched implant surface to machined, TPS, and HA surfaces: bone contact in vivo in rabbits.

PURPOSE: To evaluate the bone contact percentage around a proprietary high-temperature dual-etched (DE) implant surface (Osseotite) versus implants with machined, hydroxyapatite (HA), and titanium plasma-sprayed (TPS) surfaces. MATERIALS AND METHODS: Each implant type was placed in rabbit tibiae of the same animal and assessed at 1 to 8 weeks. Histologic sections were prepared and analyzed histomorphometrically. RESULTS: The DE implant surface achieved higher levels of bone contact percentage than the other surfaces. This enhanced contact level was apparent by 3 weeks and seen at all time intervals except 2 weeks, at which machined exceeded the DE mean. In evaluating which surface outscored the others in each individual rabbit, there was a statistically significant confidence for the DE surface (P < .001). The other 3 surfaces failed to show significance, although the numeric scores for the TPS surfaces were below random expectations and the machined scores were slightly above. There was no correlation between degree of roughness and bone contact percentage. DISCUSSION: Arbitrarily roughening the implant surface may not result in a large change in bone conductivity. The specific texture of the DE process yielded more contact, possibly as the result of better fibrin clot retention and growth factor enhancement. CONCLUSIONS: There was no advantage demonstrated in this model to an HA surface over titanium. The bone contact to the rough HA surface scored similarly to that for the TPS surface of similar roughness, and well below that for the DE titanium surface. The DE surface appeared to have an advantage in bone contact percentage, particularly in early healing in a rabbit tibia model.

Animals↗
PubMedDate not supplied

Issues and management of herpes in pregnancy.

Genital herpes simplex virus (HSV) infection during pregnancy poses a significant risk to the developing fetus and newborn. In the United States, the incidence of this sexually transmitted disease has increased since 1970. Since many women of childbearing age are infected or are becoming infected, the risk of maternal transmission of this virus to the fetus or newborn is a major health concern. This review defines the stages of herpetic infection, outlines the spectrum of maternal and neonatal infection, including rates of transmission and risks, and provides management guidelines that have been validated by appropriately conducted outcome-based research.

Antiviral Agents↗