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Biomedical subjects

K Curry

Publications and source records attributed to K Curry.

At least 19 recordsLinked to original sources
PubMed2000

Synthesis and pharmacology of new enantiopure delta(3)-4-arylkainoids.

Seven delta(3)-4-arylkainoids possessing various 4-position aromatic and heteroaromatic groups were synthesized and their apparent affinities were measured in order to explore the influences of 4-position electron density and stereochemistry on receptor affinity and specificity. Kainoids 1a-f were shown to be selective agonists at the NMDA receptor and the electron rich furanyl and thienyl analogues exhibited the highest affinities. Naphthylkainoid 1g proved to be a nonselective antagonist at the iGluRs.

Excitatory Amino Acid Agonists↗
PubMed1999

A novel fluorescent GSH-adduct binds to the NMDA receptor.

In an attempt to develop various fluorescent probes to label glutathione (GSH) receptors, we have serendipitously synthesized a probe that binds to and antagonizes the NMDA receptor. Probe 1, a GSH adduct, displaces the competitive NMDA antagonist [3H]-CGP 39653 with a higher affinity than NMDA or cysteine in rat synaptic membranes. In recording experiments from a rat cortical 'wedge' preparation, Probe 1 reversibly blocks both NMDA- and cysteine-induced depolarization. In mixed astrocyte-neuron tissue culture preparations, Probe 1 labels parts of both cell bodies as well as processes. The present data suggest that Probe 1 binds to the NMDA receptor and antagonizes channel function.

2-Amino-5-phosphonovalerate↗
PubMed1999

Methionine sulfoximine shows excitotoxic actions in rat cortical slices.

Methionine sulfoximine (MSO) is a rare amino acid. It occurs in nature or as a by-product of some forms of food processing. A notable example of the latter was a former method for bleaching wheat flour, using nitrogen trichloride, the "agene process," in use for most of the first 50 years of this century. "Agenized" flour was found to be responsible for various neurological disorders in animals, and MSO was identified as the toxic factor. The agene process was subsequently discontinued in the United States and the United Kingdom circa 1950. MSO inhibits the synthesis of both glutathione and glutamine, and it is possible that its actions on the nervous system arise from alterations in the amount or distribution of these molecules. Structurally, MSO resembles glutamate, an observation that has also raised the possibility that it might have more direct glutamate-like actions on neurons. In the present investigation, we report excitatory and toxic actions of MSO in an in vitro preparation of adult rat cortex. Field potential recordings in this preparation show that MSO application evokes a sustained depolarization, which can be blocked by the N-methyl-D-aspartate (NMDA) antagonist L-(+)-2-amino-5-phosphonovalerate (AP5). However, competition assays using MSO on [3H]CGP-39653 (DL-(E)-2-amino-4-propyl-1-phosphono-3-pentenoate) binding in rat cortical homogenates show only 20% displacement of total binding, suggesting that MSO is acting indirectly, perhaps by releasing glutamate. To investigate this possibility, we measured glutamate release during MSO application. Time course and dose-response experiments with MSO showed significant [3H]glutamate release, which was partially attenuated by AP5. To assess cellular toxicity, we measured lactate dehydrogenase (LDH) release from cortical sections exposed to MSO. MSO treatment led to a rapid increase in LDH activity, which could be blocked by AP5. These data suggest that MSO acts by increasing glutamate release, which then activates NMDA receptors, leading to excitotoxic cell death. These data suggest the possibility that MSO in processed flour had excitotoxic actions that may have been contributing factors to some human neuronal disorders.

2-Amino-5-phosphonovalerate↗
PubMed1998

Pharmacological profile of the isomers of the GluR-specific agonist ATPA.

We have synthesized the (R)- and (S)-isomers of 2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoate (ATPA) by stereochemically certain routes. Our studies in the rat cortical wedge preparation indicate that (R)-ATPA has no observable excitatory effect, while (S)-ATPA has an apparent K(D) of 16 microM. This excitatory response is unaffected by the specific N-methyl-D-aspartate (NMDA) antagonist, D-2-amino-5-phosphonopentanoic acid (DAP5) but is partially blocked by 6-nitro-sulfamoyl[f]quinoxalinedione (NBQX) at concentrations that attenuate the effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA), the effects are however reduced by the nonspecific antagonist kynurenate (KYN), indicating an interaction with a class of kainate receptor.

2-Amino-5-phosphonovalerate↗
PubMed1997

New analogues of ACPD with selective activity for group II metabotropic glutamate receptors.

In this study we have determined the pharmacology of a series of 1-aminocyclopentane-1,3-dicarboxylic acid (1,3-ACPD) analogues at cloned metabotropic glutamic acid (mGlu) receptors. The new analogues comprise the four possible stereoisomers of 1-amino-1-carboxycyclopentane-3-acetic acid (1,3-homo-ACPD) and the racemic mixture of (1RS,2RS)-1-amino-1-carboxycyclopentane-2-acetic acid (1RS,2RS-homo-ACPD), (1RS,2RS)-Homo-ACPD was shown to be a competitive mGlu2 receptor antagonist with a KB of 391 microM. (1S,3R)-Homo-ACPD and (1R,3R)-homo-ACPD were both shown to be mGlu2 receptor agonists with EC50 values of 122 and 105 microM, respectively. Compared to (S)-Glu both compounds displayed partial agonism with intrinsic activities of 79% and 47%, respectively. (1S,3S)-Homo-ACPD was also found to be a partial mGlu2 receptor agonist with an intrinsic activity of 27% compared to (S)-Glu. None of the compounds tested showed any activity at mGlu1a or mGlu4a receptors. These homo-ACPD's show a higher degree of subtype selectivity than the parent compound (1SR,3RS)-ACPD. In addition none of the compounds demonstrated any activity at ionotropic Glu receptors.

Animals↗
PubMed1996

Glutathione-induced sodium currents in neocortex.

The present report demonstrates that glutathione (GSH), a tripeptide composed of glutamate, glycine and cysteine (gamma-L-glutamyl-L-cysteinyl-glycine) and best known as a free radical scavenger, elicits a large fast depolarizing potential when applied to cortical slices. This potential is maximally larger than that produced by either NMDA or AMPA. Like AMPA, the GSH current appears to be carried by sodium ions, but cannot be blocked by the glutamate receptor antagonists AP5 or DNQX. In addition, removal of external calcium or blockade of potassium currents by TEA does not diminish the GSH-induced potential. Together, these results suggest that GSH acts through its own receptor-mediated channels, independently of the known EAA receptors, and that its receptors may be a key, and previously unknown, component of cortical excitatory neurotransmission.

Animals↗
PubMed1995

Molecular, functional, and pharmacological characterization of the metabotropic glutamate receptor type 5 splice variants: comparison with mGluR1.

The main excitatory neurotransmitter in the brain, glutamate (Glu), activates not only receptor-channels, but also receptors coupled to G-protein called metabotropic Glu receptors (mGluRs). Eight genes coding for mGluRs have been characterized to date giving rise to even more proteins due to alternative splicing phenomena. Here we characterized a splice variant of mGluR5, called mGluR5b which contains a 32 amino acid fragment inserted in the cytoplasmic tail, 50 residues after the 7th transmembrane domain. mGluR5b mRNAs are present in different regions of the adult rat brain and are expressed at a higher level than mGluR5a mRNA. Functional analysis of mGluR5a and mGluR5b revealed that they share all the properties of mGluR1a, but not those of mGluR1b or 1c. Like mGluR1a, both mGluR5a and mGluR5b activate a rapid and transient current in Xenopus oocytes. When expressed in LLC-PK1 cells, they show the same subcellular distribution as mGluR1a, and stimulate both inositol phosphate (IP) and cAMP production. Moreover, cells expressing mGluR5a or mGluR5b, like those expressing mGluR1a have a higher basal PLC activity that is not inhibited by glutamate-pyruvate transaminase (GPT), suggesting that these receptors have an intrinsic activity. Interestingly, the pharmacological profiles of mGluR5a and b are identical, but different from that of mGluR1a. Most agonists, except glutamate, are more potent on mGluR5a/b than on mGluR1a. Interestingly, the mGluR1a antagonists MCPG and 4CPG have no effect on mGluR5a/b; 4C3HPG which is a full antagonist at mGluR1a is a partial agonist at mGluR5a/b. These results indicate that the long C-terminal intracellular domain present only in mGluR1a and mGluR5a/b, although not well conserved, is likely to be involved in the specific functional properties of these receptors. Although the ligand recognition sites of mGluR5a/b and mGluR1a are highly conserved, these receptors have different pharmacology.

Alternative Splicing↗
PubMed1994

Pharmacological characterization of metabotropic glutamate receptors in several types of brain cells in primary cultures.

Several cDNAs coding for metabotropic glutamate receptors (mGluR1-7) have now been isolated. mGluR1 and -5 are positively coupled to phospholipase C, whereas mGluR2, -3, -4, -6, and -7 are negatively coupled to adenylyl cyclase (AC) when they are expressed in Chinese hamster ovary or baby hamster kidney cells. However, the exact transduction mechanisms of these receptors in their natural environment remain to be determined. In a previous work, we demonstrated that striatal neurons in primary culture expressed a mGluR that is negatively coupled to AC and that has a pharmacology different from that of mGluR2. In the present study, the pharmacology of mGluRs negatively coupled to AC in several neuronal types and in glial cells was compared with the pharmacology of mGluR2, -3, and -4. Like striatal neurons, cerebral cortical neurons express a mGluR that is able to inhibit AC both in intact cells and in membrane preparations, via a pertussis toxin-sensitive G protein. This mGluR has a pharmacological profile similar to that of mGluR3, because quisqualate is active at relatively low concentrations (EC50 < 100 microM). Similar experiments revealed that cerebellar granule cells expressed mGluR2-like and mGluR4-like receptors. Striatal glial cells also expressed a mGluR negatively coupled to AC via a pertussis toxin-sensitive G protein. However, only glutamate and aspartate, and not quisqualate, 2-(carboxycyclopropyl)glycine, trans-1-aminocyclopentane-1,3-dicarboxylate, or L-2-amino-4-phosphonobutyrate, were agonists for this glial mGluR. This pharmacology is different from that of any cloned mGluR. Reverse transcription associated with polymerase chain reaction revealed that mGluR2 and mGluR3 mRNAs are present in striatal, cortical, and cerebellar neurons but not in striatal glial cells. Interestingly, mGluR4 mRNA was found at a high level in cerebellar granule cells and at a lower level in cortical neurons and glial cells. However, the mGluR4-specific agonist L-2-amino-4-phosphonobutyrate was found to inhibit AC very slightly in granule cells only. In conclusion, our data show that mGluR2- and mGluR3-like receptors can directly inhibit AC in neurons, and they raise the question of whether mGluR4 is really negatively coupled to AC in its normal environment. We also present evidence for a new mGluR subtype expressed in glial cells.

Adenylate Cyclase Toxin↗
PubMed1992

Characterization of a metabotropic glutamate receptor: direct negative coupling to adenylyl cyclase and involvement of a pertussis toxin-sensitive G protein.

We have characterized a G-protein-coupled glutamate receptor in primary cultures of striatal neurons. Glutamate, quisqualate, or trans-1-aminocyclopentane-1,3-dicarboxylate inhibited by 30-40% either forskolin-stimulated cAMP production in intact cells or forskolin plus vasoactive intestinal peptide-activated adenylyl cyclase assayed in neuronal membrane preparations. These inhibitory effects were suppressed after treatment of striatal neurons with Bordetella pertussis toxin, suggesting the involvement of a heterotrimeric guanine nucleotide-binding protein (G protein) of the G(i)/G(o) subtype. The pharmacological profile of this glutamate receptor negatively coupled to adenylyl cyclase was different from that of the metabotropic Qp glutamate receptor coupled to phospholipase C in striatal neurons and from that of the recently cloned "mGluR2" glutamate receptor, which is negatively coupled to adenylyl cyclase when expressed in non-neuronal cells.

Adenylate Cyclase Toxin↗
PubMed1992

The relationship between extended periods of immobility and decubitus ulcer formation in the acutely spinal cord-injured individual.

Several variables may influence the development of decubitus ulcers during the acute treatment phase following spinal cord injury. Three independent variables were studied: level of injury, completeness of injury and length of time immobilized. Of these, length of immobilization exceeding 6 hours was associated with subsequent development of a sacral or occipital decubitus at a statistically significant level (p = .0094). The presence of a complete injury was associated with decubitus formation at a noticeable but statistically insignificant level (p = .0759). Cervical injuries were not associated with an increased rate of decubitus formation. Results suggested that initial treatment of acute spinal cord injuries should include the use of pressure relieving maneuvers or devices as soon as possible, especially in patients with anticipated extensive immobilization. Recognizing that risk of decubitus formation increases with immobilization time, the period of time involved in initial diagnosis and intervention should be kept to a minimum. This is particularly true in patients with complete spinal cord injuries.

Adolescent↗
PubMed1992

Both enantiomers of 1-aminocyclopentyl-1,3-dicarboxylate are full agonists of metabotropic glutamate receptors coupled to phospholipase C.

We tested the effects of two enantiomers of a glutamate analogue, (trans)-1-aminocyclopentyl-1,3-dicarboxylate (t-ACPD), in striatal and cerebellar neurons in primary culture, as well as in Xenopus oocytes injected with cerebellar rat RNA. In the presence of MK-801, to avoid N-methyl-D-aspartate receptor activation, and 3 microM tetrodotoxin, both enantiomers [(1R,3S)- and (1S,3R)-t-ACPD] stimulated inositol phosphate (InsP) formation both in striatal neurons after 9-11 days in vitro [EC50, 3.7 +/- 1.1 microM, three experiments, and 33 +/- 7.5 microM, three experiments; maximal stimulatory effects, 252 +/- 15%, 13 experiments, and 269 +/- 15% of basal InsP formation, 14 experiments, for (1R,3S)- and (1S,3R)-t-ACPD, respectively] and in cerebellar granule cells after 9-11 days in vitro [EC50, 50 +/- 18 microM, four experiments, and 307 +/- 92 microM, four experiments; maximal stimulatory effects, 401 +/- 71%, eight experiments, and 423 +/- 75% of basal InsP formation, eight experiments, for (1R,3S)- and (1S,3R)-t-ACPD, respectively]. These effects were not additive, indicating that both enantiomers acted at the same receptor molecule. When we monitored t-ACPD-induced increases in intracellular Ca2+ concentration ([Ca2+]i) with fura-2 ratio-imaging, we found that both enantiomers could elicit similar increase in [Ca2+]i, in the presence of 1 microM MK-801 and 3 microM tetrodotoxin; these effects were also observed in the absence of external Ca2+. Moreover, in Xenopus oocytes injected with adult rat cerebellar RNA, both drugs elicited oscillatory increases of a Ca(2+)-dependent chloride conductance, with similar efficacy, with (1R,3S)-t-ACPD being the more potent isomer. These data are in contradiction to previous reports showing that, in "immature" cerebellar neurons and adult hippocampal slices, (1S,3R)-t-ACPD was either the only active enantiomer or a full agonist of metabotropic receptors, with (1R,3S)-t-ACPD being ineffective or a partial agonist. However, performing these experiments in immature (2-3 days in vitro) striatal or cerebellar neurons, we found that only (1S,3R)-t-ACPD was active in stimulating [Ca2+]i.

Animals↗
PubMed1991

The actions of a conformationally restricted analogue of aspartic acid on mammalian spinal neurones.

The effects of the 4 stereoisomers of 1-aminocyclopentane-1,2-dicarboxylic acid (CPA), a conformationally restricted analogue of aspartic acid, have been examined on spinal dorsal horn neurones of the rat in vivo. Unlike the corresponding 1,3-dicarboxylate compounds which are glutamate analogues and markedly excitatory, the CPA isomers had no evident excitatory actions of their own. Three were weak and non-specific antagonists of other amino acid-induced excitations, while the (+)-trans isomer had a slight potentiating effect.

Action Potentials↗
PubMed1991

Rigid analogues as probes of excitatory amino acid receptors.

The classes of compounds to be discussed are based on rigid analogues of glutamic and aspartic acids. The glutamate analogue 1-amino-1,3-cyclopentane dicarboxylic acid (1,3-ACPD) exists as two enantiomeric pairs of geometric isomers. The absolute configurations were assigned and the compounds were found to differentiate between the kainic acid (KA) and N-methyl-D-aspartic acid (NMDA) receptor subtypes when applied iontophoretically to hippocampal CA1 pyramidal neurones. The results indicate a high degree of specificity for the interaction of D-cis-1,3-ACPD with the NMDA receptor, while the remaining three isomers of 1,3-ACPD were KA-like in their action. The results are augmented with binding studies and patch clamp analysis. The second class of compound is the closely related aspartate analogue 1-amino-1,2-cyclopentane dicarboxylic acid (1,2-ACPD). The geometric isomers have been examined and found to be somewhat less active than their 1,3-ACPD counterparts; however, the cis isomer does have antagonistic properties against quisqualate (QA) evoked excitation. The results indicate that while the three-dimensional arrangement of functional groups is important for the activation of receptor subtypes, other considerations must be made, including stereochemistry and receptor affinity for sterically hindered analogues of excitatory amino acids.

Animals↗
PubMed1990

Quinolinate activation of N-methyl-D-aspartate ion channels in rat hippocampal neurons.

The cell attached configuration of the patch clamp method has been used to determine the single channel properties of the ion channel coupled to activation of the N-methyl-D-aspartate (NMDA) receptor by the endogenous NMDA agonist quinolinate. Openings of the NMDA channel were recorded from cultured CA1 hippocampal neurons over a hyperpolarizing potential range from cell resting potential. The slope conductance of the channel was 39 pS with 75 microM quinolinate, 1.8 mM Ca2+ and no Mg2+ in the patch pipette. The mean channel open times were decreased with hyperpolarization in an exponential manner with a mean slope of 0.6 ms/20 mV. Addition of Mg2+ to the pipette (at 30 microM) caused the mean open time, at a potential of -100 mV, to be decreased to a value about one-third that of control. The mean open times with quinolinate as the agonist were shorter for all potentials studied compared with activation of the NMDA receptor with NMDA or D-cis-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD). Both the mean open times and the channel amplitudes were significantly altered when the bath temperature was decreased; the Q10 values for both quantities were in excess of 2.8.

Animals↗
PubMed1990

Single channel properties of the N-methyl-D-aspartate receptor channel using NMDA and NMDA agonists: on-cell recordings.

The cell-attached patch-clamp mode has been applied in cultured rat hippocampal neurons to record single channel currents through the ion channel which is coupled to activation of the N-methyl-D-aspartate (NMDA) receptor. A channel, with a conductance of 37 pS, was studied with either NMDA or D-cis-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) in the patch pipette. The mean open time of the channels with NMDA in the pipette was near 5 ms at -80 mV and was diminished about 0.7 ms for each 20 mV of hyperpolarization. The mean open times with ACPD in the pipette were longer at all voltages studied and for both agonists the mean open times showed an exponential dependence on patch potential. Distributions for the channel open times were generally well-fit with single exponentials, whereas distributions for closed times required two-component fits. In some instances, the open distributions also showed a second, rapid time component. When Mg2+ was included in the pipette (40 or 100 microM), the mean open times were significantly diminished with the effect increasing with the magnitude of the hyperpolarization. Both the amplitudes and mean open times of the NMDA channel were strongly modulated by temperature with Q10 values in excess of 2.5.

Animals↗
PubMed1990

Contingent reinforcement effects on movement responses of prison inmates to the Holtzman Inkblot Technique.

Prison inmates were administered the Holtzman Inkblot Technique (HIT) under conditions of either verbal or nonverbal reinforcement of movement responses. Overall, there were no differences among the verbal, nonverbal, and control groups. Inmates charged with violent crimes were found to give the fewest movement responses. With crime category controlled, more movement responses were given under nonverbal conditions. There were no sex differences for movement responses but testing time increased significantly when administered by the female examiner.

Adolescent↗
PubMed1989

Executive roundup. Surviving the cash flow crunch.

With today's dual pressures demanding quality health care at more affordable prices, it's little wonder many hospital executives are worried about their institutions' financial health--and even their jobs. Still, many of these officials are trying to keep a positive face on things. In part, they express the hope that creative product supply systems and better overall communication with vendors will generate efficiencies and help offset dwindling reserves. The following excerpts from a discussion among hospital authorities shed some light on the thought processes behind those beliefs and attitudes. The views, offered at a recent meeting sponsored in part by Medline Industries, are edited here as a round-up of selected opinion on issues affecting suppliers.

Commerce↗