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W J Strittmatter

Publications and source records attributed to W J Strittmatter.

87 records · Page 5Linked to original sources
PubMed1983

Protease inhibitors implicate metalloendoprotease in synaptic transmission at the mammalian neuromuscular junction.

Metalloendoproteases have been implicated in the calcium-dependent exocytosis of histamine from mast cells and in the calcium-dependent fusion of myoblasts. Because metalloendoproteases have also been identified in nervous tissue, we investigated the possibility that these proteases may be involved in neurotransmitter release at mammalian synapses. End-plate potentials were recorded intracellularly from mouse diaphragm/phrenic nerve preparations in vitro. The amplitude of the endplate potentials were reduced by as much as 90% during bath application of phosphoramidon, a specific inhibitor of metalloendoproteases, and by carbobenzoxy-dipeptide-amide synthetic substrates for metalloendoproteases. Only those synthetic dipeptides in which the amino group of the peptide bond was provided by a bulky hydrophobic amino acid, such as phenylalanine or leucine, which are substrates for metalloendoproteases, reduced synaptic transmission. Synthetic substrates in which proline or glycine provided the amino group of the peptide bond, which are not metalloendoprotease substrates, had little or no effect on the amplitude of end-plate potentials. The ability of synthetic substrates to reduce synaptic transmission was also dependent on the amino acid that provided the carboxyl group of the peptide bond, with glycine being more effective than tyrosine or serine. In addition, synthetic dipeptides with free carboxyl or amino termini, which have a low affinity for metalloendoproteases, also had little effect on synaptic transmission. The inhibition of synaptic transmission by phosphoramidon and the synthetic substrates occurred within 2 to 3 min and was completely reversible. Neither phosphoramidon nor the synthetic substrates altered the dose-response characteristics of the postsynaptic membrane to bath-applied carbachol. These results suggest that synaptic transmission requires the activity of a metalloendoprotease in the presynaptic nerve terminal and that proteolysis may be an important step during neurotransmitter exocytosis.

Animals↗
PubMed1981

Regulation of the beta-adrenergic receptor by methylation of membrane phospholipids.

Stimulation of the beta-adrenergic receptor increases the enzymatic methylation of membrane phospholipids. Increased synthesis of phosphatidyl-N-monomethylethanolamine by methyltransferase I increases fluidity and enhances the ability of the beta-adrenergic receptor to couple with adenylate cyclase. The number of beta-adrenergic receptors can be regulated by the rate of synthesis and of degradation of phosphatidylcholine formed by transmethylation.

Animals↗
PubMed1981

Phospholipid methylation: a possible mechanism of signal transduction across biomembranes.

The conversion of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) is catalyzed by two methyltransferases with S-adenosylmethionine as the methyl donor. PC formed by transmethylation is further metabolized by phospholipase A2. The synthesis and degradation of methylated phospholipids are involved in regulating the number of the beta-adrenergic receptors and their coupling to adenylate cyclase in rat reticulocytes, HeLa cells, and rat astrocytoma cells. Methylation of the phospholipids in these cells is stimulated by binding of agonists to the beta-adrenergic receptors. Accumulation of phosphatidyl-N-monomethylethanolamine causes an increase in membrane fluidity and enhances the coupling of the receptors to adenylate cyclase. Agents that inhibit phospholipid methylation decrease the number of receptors in intact HeLa cells, while increased phospholipid methylation unmasks cryptic receptors. Conversely, the degradation of methylated phospholipids appears to be closely associated with the desensitization of the beta-adrenergic receptors following prolonged stimulation with isoproterenol. Inhibition and stimulation of phospholipase A2 causes inhibition and stimulation of this desensitization process.

Adenylyl Cyclases↗
PubMed1979

Phospholipid methylation unmasks cryptic beta-adrenergic receptors in rat reticulocytes.

The effect of phospholipid methylation on the number of beta-adrenergic receptor binding sites was examined in rat reticulocyte membranes. Stimulation of phosphatidylcholine synthesis by the introduction of the methyl donor S-adenosyl-L-methionine into reticulocyte ghosts increased the number of beta-adrenergic receptor sites. The appearance of beta-adrenergic binding sites was dependent on the formation of phosphatidylcholine by the enzyme that converts phosphatidyl-N-monomethylethanolamine from phosphatidylethanolamine. Both the synthesis of phosphatidylcholine and the unmasking of cryptic receptors were time and temperature dependent and did not occur in the presence of the methyl transferase inhibitor, S-adenosyl-L-homocysteine.

Animals↗
PubMed1979

beta-Adrenergic receptor agonists increase phospholipid methylation, membrane fluidity, and beta-adrenergic receptor-adenylate cyclase coupling.

The beta-adrenergic agonist L-isoproterenol stimulated the enzymic synthesis of phosphatidyl-N-monomethylethanolamine and phosphatidylcholine in rat reticulocyte ghosts containing the methyl donor S-adenosyl-L-methionine. The stimulation was stereospecific, dose-dependent, and inhibited by the beta-adrenergic agonist propranolol. The addition of GTP inside the resealed ghosts shifted the dose-response of phospholipid methylation by L-isoproterenol to the left by 2 orders of magnitude. Direct stimulation of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] with sodium fluoride or cholera toxin did not increase the methylation of phospholipids. At a concentration of S-adenosyl-L-methionine that stimulates synthesis of phosphatidyl-N-monomethylethanolamine, the activity of isoproterenol-sensitive adenylate cyclase was increased 2-fold without changes in the basal activity of adenylate cyclase and the number of beta-adrenergic receptors. The increase of phospholipid methylation by L-isoproterenol decreased membrane viscosity and increased translocation of methylated lipids. These findings indicate that enhancement of phospholipid methylation by L-isoproterenol decreases membrane microviscosity and thus increases lateral movement of the beta-adrenergic receptors and coupling with adenylate cyclase.

Adenylyl Cyclases↗
PubMed1978

Beta adrenergic stimulation of protein carboxymethylation and amylase secretion in rat parotid gland.

Protein carboxymethylase (S-adenosyl-l-methionine:protein-O-methyltransferase, EC 2.1.1.24) transfers methyl groups from S-adenosylmethionine to protein carboxyl groups. This cytosolic enzyme is found in highest concentration in secretory tissue and methylates membrane proteins. Stimulation of the parotid gland by catecholamines rapidly and reversibly increases protein carboxymethylase activity and methyl acceptor capacity of proteins in parotid homogenates. Isoproterenol was effective at concentrations causing amylase release in vivo and in vitro. Both enzyme activity and methyl acceptor capacity of proteins increased within 5 min, continued to increase for 30 min and then declined to control values within 60 min. The response to isoproterenol was stereospecific. The action of isoproterenol could be blocked by the beta adrenergic antagonist propranolol, while the alpha adrenergic agonist phenylephrine did not stimulate the enzyme or increase methyl acceptor proteins. Methyl acceptor proteins have been partially characterized by polyacrylamide gel electrophoresis. Although many proteins in the parotid are methylated, only two groups of methylated proteins increase after stimulation by isoproterenol.

Amylases↗
PubMed1977

[3H]dihydroergocryptine binding in rat brain.

[3H]dihydroergocryptine (DHE) appears to bind to alpha-adrenergic receptor sites in rabbit uterine membranes. We have characterized the binding of [3H]DHE to membranes prepared from rat cerebral cortex. alpha-Adrenergic agents were less potent and dopamine and serotonin, more potent, in displacing brain DHE binding than in uterus. Furthermore brain DHE binding sites demonstrated less stereospecificity for catecholamines than sites in uterus. Dopamine displaced DHE binding with about the same potency in cerebellar and cerebral cortical membranes, but was 10 times as potent in displacing DHE binding in the striatum. The binding of [3H]DHE in brain is complex and differs significantly from the rabbit uterus. There are two possible explanations for this discrepancy. [3H]DHE may bind a single site in brain with properties differing from known peripheral adrenergic receptors or DHE may bind to multiple sites in brain, sites which may or may not represent other neurotransmitter receptors.

Animals↗
PubMedDate not supplied

Binding of IgG to amyloid beta A4 peptide via the heavy-chain hinge region with preservation of antigen binding.

Amyloid beta A4 peptide is found in the extracellular region of the senile plaque and in the angiopathy of Alzheimer's disease. Several other proteins, including IgG, also reside in these abnormal structures. In an attempt to understand how these structures are assembled and to determine how proteins are recruited, interactions of various proteins with synthetic beta A4 peptide have been examined in vitro. Purified IgG binds directly to synthetic beta A4 peptide with high avidity. The domain between amino acids 12-28 of beta A4 binds IgG. beta A4 peptide binds the hinge region of the immunoglobulin heavy chain, and preserves the ability of the immunoglobulin to bind antigen. A protein which does not bind directly to beta A4 peptide can be targetted to the senile plaque and angiopathy by binding to IgG, which avidly binds beta A4 peptide.

Amyloid beta-Peptides↗
PubMedDate not supplied

Will neurotrophic agents be harmful in Alzheimer's disease?

The thesis that neurotrophic therapy in Alzheimer's disease may exacerbate the pathological state merits careful experimental verification. We are concerned about prematurely dismissing an important avenue of potential therapy which would provide a trophic stimulus to compensate for enhanced proteolysis and the deposition of A4 amyloid peptide.

Alzheimer Disease↗