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Biomedical subjects

G Lynch

Publications and source records attributed to G Lynch.

At least 433 records · Page 24Linked to original sources
PubMed1981

Phosphorylation-mediated changes in pyruvate dehydrogenase activity influence pyruvate-supported calcium accumulation by brain mitochondria.

Changes in the activity of pyruvate dehydrogenase [pyruvate:lipoamide oxidoreductase (decarboxylating and acceptor-acetylating), EC 1.2.4.1, PDH], elicited by inhibition of the phosphorylation of its 40,000 Mr alpha-subunit, were compared with changes in pyruvate-supported calcium accumulation by rat brain mitochondria. Dichloroacetate (DCA) produces concentration-dependent inhibition of the phosphorylation of intramitochondrial PDH alpha-subunit, which is accompanied by stimulation of PDH activity and calcium accumulation. DCA did not affect succinate- or ATP-supported mitochondrial calcium accumulation. The concentration of DCA giving half-maximal inhibition of the phosphorylation was almost identical to that giving half-maximal stimulation of PDH activity and calcium accumulation. PDH activity and pyruvate-supported calcium accumulation showed similar dependence on pyruvate concentration with respective apparent affinities for pyruvate of 40 microM and 30 microM, and both activities exhibited positive cooperativity. DCA modified only the maximal activity of PDH or the maximal calcium DCA modified only the maximal activity of PDH or the maximal calcium accumulation without changing either the apparent affinities for pyruvate or calcium or the Hill coefficients. These data provide evidence that calcium accumulation by mitochondria is tightly linked to PDH activity and that changes in the phosphorylation of the PDH alpha-subunit can be reflected in changes in the calcium-buffering ability of mitochondria. This suggests a possible mechanism by which a variety of manipulations, such as repetitive synaptic stimulation, can alter the regulation of internal calcium levels.

Adenosine Triphosphate↗
PubMed1981

Phase II evaluation of metoprine with leucovorin rescue in patients with advanced colorectal carcinoma.

In a phase II trial 24 patients with measurable metastatic colorectal carcinoma were treated every 2 weeks with high-dose metoprine at 175 mg/m2 and leucovorin rescue. Hematologic toxicity was mild; the limiting toxicity was CNS, occurring in 54% of the patients. No responses were observed, but four patients had disease stabilization. High-dose metoprine with leucovorin rescue appears ineffective in previously treated patients with colorectal carcinoma in the dose and schedule used in this study.

Adult↗
PubMed1980

Accelerated rates of synaptogenesis by "sprouting" afferents in the immature hippocampal formation.

Light and electron microscopic methods were used to study the rate with which undamaged afferents sprout into and form synapses within denervated dendritic zones in the immature rat brain. The middle and outer molecular layers of the dentate gyrus were deafferented by ablation of the ipsilateral entorhinal cortex in 14-day-old rats, and the extension of the commissural projections, which are normally restricted to the inner molecular layer, into the denervated territory was studied by light microscopic autoradiographic tracing methods. Collateral growth was noted as early as 13 hours after the lesion and was found to reach throughout the middle and outer molecular layers by 48 hours postlesion. Quantitative analyses (grain counts) revealed that the addition of commissural fibers and terminals to the denervated zones proceeded extremely rapidly up to 72 hours after the removal of the entorhinal cortex, but slowed markedly thereafter. Electron microscopic procedures were used to assess the rate at which synapses formed during this period and yielded the following information: 1) The density of intact synapses fell to below 20% of normal values within 20 hours of the lesion, 2) reinnervation began before 30 hours postlesion, and 3) the rate at which synapses were added to deafferented middle molecular layer was much more rapid from 20-96 hours postlesion than is observed in this zone during normal development. Furthermore, the sprouting of the inner molecular layer afferents into the middle molecular layer did not retard the pace of synaptogenesis in their normal target region. These results suggest that intrinsic limitations in the capacity of axons and dendrites are not responsible for determining the rate of synaptogenesis in the developing hippocampus. It is proposed instead that existing synapses (or terminals and spines) tend to suppress the formation of new contacts such that the local density of connections regulates the speed with which further innervation occurs.

Animals↗
PubMed1980

Trifluoperazine inhibits hippocampal long-term potentiation and the phosphorylation of a 40,000 dalton protein.

Brief high frequency stimulation induces long-term potentiation (LTP) and changes in the endogenous phosphorylation of a 40,000 dalton protein in the hippocampus in a calcium-dependent manner. In the present paper we report that 40 microM trifluoperazine (TFP), a phenothiazine that binds calmodulin and blocks its activity, inhibits LTP in the hippocampal slice. In addition, calmodulin stimulates and TFP inhibits the phosphorylation of the 40,000 dalton protein (as well as that of several other proteins) in a dose-dependent fashion.

Animals↗
PubMed1980

Regulation of hippocampal glutamate receptors: evidence for the involvement of a calcium-activated protease.

Specific [3H]glutamate binding to rat hippocampal membranes and the calcium-induced increase in this binding are markedly temperature-sensitive and are inhibited by alkylating or reducing agents as well as by various protease inhibitors. N-Ethylmaleimide, chloromethyl ketone derivatives of lysine and phenylalanine, and tosylarginine methyl ester decrease the maximum number of [3H]glutamate binding sites without changing their affinity for glutamate. Preincubation of the membranes with glutamate does not protect the glutamate "receptors" from the suppressive effects of these agents. The proteases trypsin and alpha-chymotrypsin increase the maximum number of [3H]glutamate binding sites. The effects of calcium on glutamate binding are different across brain regions. Cerebellar membranes are almost insensitive whereas hippocampal and striatal membranes exhibit a strong increase in the number of binding sites after exposure to even low concentrations of calcium. These results suggest that an endogenous membrane-associated thiol protease regulates the number of [3H]glutamate-associated thiol protease regulates the number of [3H]glutamate binding sites in hippocampal membranes and that this is the mechanism by which calcium stimulates glutamate binding. The possibility is discussed that the postulated mechanisms participate in synaptic physiology and in particular may be related to the long-term potentiation of transmission found in hippocampus under certain conditions.

Alkylating Agents↗
PubMed1980

Low-temperature induction of calcium-dependent protein phosphorylation in blood platelets.

Exposure to low temperature causes platelets to change shape in a manner similar to the shape change that precedes secretagogue-induced serotonin release. Previous studies have shown that two proteins, of approximately 20,000 and approximately 40,000 Mr, become phosphorylated before secretion. We have investigated whether low temperature can induce phosphorylation of these proteins and/or serotonin secretion. The data indicate that low-temperature-induced shape change has no requirement for extracellular calcium, whereas phosphorylation of the two proteins and subsequent serotonin release both have strong calcium requirements. Because cold treatment is thought to influence platelet shape through an effect on microtubules, the events in the shape change-release sequence would seem to be ordered as follows: microtubule disassembly leads to shape change leads to protein phosphorylation leads to secretion.

Animals↗
PubMed1980

Characterization of corticosterone-induced protein synthesis in hippocampal slices.

Corticosterone significantly increases the incorporation of [3H]leucine into specific cytosol protein(s) isolated from in vitro hippocampal slices prepared from adult male albino rats. The present study showed that in slices coincubated with glucocorticoid plus a protein synthesis inhibitor (1 mM-cycloheximide), no such enhancement of amino acid incorporation was observed, suggesting that the hormone acts in the hippocampus to increase de novo protein synthesis. Further experiments demonstrated that the steroid-induced protein synthesis was first detectable (+ 5.7%) following a 30-min exposure of slices to corticosterone; slices incubated for 1 or 2 h both showed a 12% increase in synthesis of the affected protein(s) when compared with controls. In an attempt to determine whether the glucocorticoid alteration of protein metabolism was receptor-mediated, hippocampal slices were also incubated with 10 nM-progesterone, a steroid known to compete for corticosterone binding to its cytosol receptor. Progesterone alone, which does not translocate cytoplasmic receptors to the nucleus, did not alter hippocampal protein metabolism and effectively blocked the induction by corticosterone of the 54K protein(s). These studies provide evidence that in the rat hippocampus corticosterone interacts with high-affinity steroid receptors to regulate the synthesis of specific protein(s).

Animals↗
PubMed1980

Paired-pulse and frequency facilitation in the CA1 region of the in vitro rat hippocampus.

1. Several types of facilitation of evoked synaptic responses were investigated in the CA1 region of the in vitro rat hippocampus. Homosynaptic paired-pulse facilitation and heterosynaptic frequency facilitation were characterized and found to be differentiable processes on the basis of several characteristics.2. Paired-pulse facilitation, which occurs when the same input is stimulated twice in rapid succession, is manifested as an increase in both the extracellularly recorded population spike and the field e.p.s.p., and is specific to the set of afferents excited by the first impulse. Responses to other excitatory afferents show no facilitation by a heterosynaptic conditioning pulse.3. At intervals less than 200 msec, the degree of facilitation produced by a preceding impulse appears to decline as a first order exponential function of time. Facilitation is increased by lowering calcium or raising magnesium concentrations in the bathing medium, with no apparent change in the time constant of the decay process.4. The phenomenon that has sometimes been termed frequency facilitation, and which occurs during the early phase of repetitive stimulation, appears to be an extension of paired-pulse facilitation. It is seen as an increase in amplitude of both the e.p.s.p. and population spike in response to stimulation of homosynaptic inputs, can be predicted with fair accuracy by assuming that the residual paired-pulse facilitation produced by each impulse adds linearly with that from previous impulses, and is affected by calcium and magnesium ions in the same manner as is paired-pulse facilitation. These two types of facilitation, which apparently share a common mechanism, are termed synaptic or primary facilitation.5. Another type of facilitation, which we suggest might more properly be called frequency facilitation, develops slowly during the course of repetitive stimulation. It is the result of an increase in cell firing in response to any excitatory input, either homo- or heterosynaptic, at time points at which the field e.p.s.p. is typically depressed.6. Increases in the potassium concentration of the perfusion medium produce effects similar to those observed with frequency facilitation; stimulation-evoked increases in the extracellular concentration of this ion are hypothesized to underlie this type of generalized facilitation.

Animals↗