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At least 217 records · Page 12Linked to original sources
PubMed1992

Substrate inhibition of acetylcholinesterase: residues affecting signal transduction from the surface to the catalytic center.

Amino acids located within and around the 'active site gorge' of human acetylcholinesterase (AChE) were substituted. Replacement of W86 yielded inactive enzyme molecules, consistent with its proposed involvement in binding of the choline moiety in the active center. A decrease in affinity to propidium and a concomitant loss of substrate inhibition was observed in D74G, D74N, D74K and W286A mutants, supporting the idea that the site for substrate inhibition and the peripheral anionic site overlap. Mutations of amino acids neighboring the active center (E202, Y337 and F338) resulted in a decrease in the catalytic and the apparent bimolecular rate constants. A decrease in affinity to edrophonium was observed in D74, E202, Y337 and to a lesser extent in F338 and Y341 mutants. E202, Y337 and Y341 mutants were not inhibited efficiently by high substrate concentrations. We propose that binding of acetylcholine, on the surface of AChE, may trigger sequence of conformational changes extending from the peripheral anionic site through W286 to D74, at the entrance of the 'gorge', and down to the catalytic center (through Y341 to F338 and Y337). These changes, especially in Y337, could block the entrance/exit of the catalytic center and reduce the catalytic efficiency of AChE.

Acetylcholinesterase↗
PubMed1990

Paralysis and growth of the musculoskeletal system in the embryonic chick.

Avian embryos can be completely paralyzed by injection of neuromuscular-blocking agents. We used a single injection of decamethonium iodide to paralyze embryos at 7, 8, or 10 days of incubation and analyzed the growth of individual bones (clavicle, mandible, ulna, femur, tibia, humerus) and of individual muscles that act upon some of those bones (clavicular and sternal heads of m. pectoralis, and mm. biceps brachii, depressor mandibulae, pseudotemporalis, and adductor externus). Growth of the bones is not equally affected by paralysis. Only 27% of clavicular growth (by mass) but 77% of mandibular growth occurred in paralyzed embryos, whereas the four long bones exhibited 52-63% of their normal growth. Analysis of muscle weight, fiber length and physiological cross-sectional area (weight/fiber length) indicate that there was greater reduction of the muscles acting on the limbs than of those acting on the mandible, i.e., diminished growth of the skeleton is correlated with reduced muscular activity. Specific retardation of clavicular growth is due to fusion of sternal rudiments and collapse of the thorax, as well as virtual absence of the musculature that normally attaches to the clavicle. We discuss these results in the light of intrinsic and extrinsic factors governing growth of the embryonic skeleton. Paralysis reduces skeletal growth by reducing both the movements taking place in ovo, and the loads imposed on the bones by muscle contraction, changes that represent alterations in the mechanical environment of the skeleton.

Animals↗
PubMed2000

Mechanical modulation of tenascin-C and collagen-XII expression during avian synovial joint formation.

The objective of this study was to investigate how temporal and spatial patterns of characteristic extracellular matrix molecules are altered in the absence of normal functional skeletal muscle contractions during avian synovial joint development. By using in situ detection of protein and mRNA expression in developing avian feet and femorotibial joints from a wide range of developmental stages, we demonstrate that the morphological abnormalities that result from embryonic immobilization are associated with altered patterns of tenascin-C and collagen-XII expression within developing joint structures. As the joints fuse in immobilized embryos, the cells of the presumptive articular surface differentiate from flattened fibroblasts to more rounded chondrocytes and collagens XII and I are no longer detected at sites of complete joint fusion. Although the expression of collagen XII persists at normal levels elsewhere within the immobilized joint, tenascin-C expression is diminished within the chondroepiphysis, synovium, and tendons, as well as within the remains of the fibrous articular surface. This effect is most notable for the shortest tenascin variant (Tn190) within the chondroepiphysis and the largest variant (Tn230) within tendons, synovium, and the fibrous surface layer of the joint. This study thus provides in vivo support of previous in vitro work that suggests that tenascin expression is sensitive to external changes in mechanical loading environment. However, these data do not support a similar conclusion for collagen XII during early development.

Animals↗
PubMed2006

Effect of in ovo immobilization on development of chick hind-limb articular cartilage: an evaluation using micro-MRI measurement of delayed gadolinium uptake.

To examine the effect of immobilization on the development of articular cartilage, we assessed glycosaminoglycan (GAG) content in the chick articular surface by delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). Chick embryos were paralyzed by decamethonium bromide (DMB) from day 10 to either day 13 or day 16. The GAG content of the chick knee was compared with that of nonparalyzed chick embryos. Histologic analysis was unable to quantify GAG content; however, dGEMRIC demonstrated that GAG content was higher in the femoral condyles of the nonparalyzed embryos on day 13, and on day 16 the GAG content was lower in both the femoral condyles and the tibial plateaus of the nonparalyzed embryos. These results suggest that paralysis delays embryonic hind-limb development. Osteoblastic activity at the cartilage canal, as demonstrated by staining for alkaline phosphatase (ALP), was present only in the nonparalyzed chick embryos on day 16. The GAG content of the cartilage decreased when the cartilage canals began to form on day 16. The effect of immobilization on hind-limb development was indicated by the differences in the GAG content of the cartilage anlage measured by dGEMRIC in the developing knee joint of paralyzed and nonparalyzed embryonic chicks.

Animals↗
PubMedDate not supplied

Myasthenia gravis: a personal view of pathogenesis and mechanism, part 2.

A review of our current knowledge of the etiology and pathogenesis of myasthenia gravis is presented, with particular emphasis on the immunological aspects of the disease. Part 1, published in the January/February issue of MUSCLE & NERVE, dealt with the clinical and genetic features of myasthenia gravis which led to the autoimmune theory of the etiology of the disease. Part 2, which appears in this issue, provides a review of the dysfunction of physiology, pharmacology, and structure of the neuromuscular junction in myasthenia gravis, and the part played by the autoimmune process.

Autoimmune Diseases↗
PubMed1995

Response of guinea pig smooth and striated urethral sphincter to cromakalim, prazosin, nifedipine, nitroprusside, and electrical stimulation.

Prazosin (an alpha-1-adrenergic blocker) and cromakalim (potassium channel opener), given alone, induced significant fatigue of the urethral sphincter at a concentration of 10(-4) M; both drugs combined achieved a significant sphincteric fatigue at a concentration of 10(-5) M each. To 10(-4) M hexamethonium (ganglionic smooth muscle blocker) and 10(-4) M decamethonium (nicotinic blocker of striated muscle) the striated urethral sphincter responded like striated muscle with no detectable function of its smooth muscle component. Therefore, the striated component seems to play a dominant role in sphincteric function. With calcium depletion or in the presence of a calcium channel blocker (10(-4) M nifedipine) the urethral sphincter showed a relative enhancement of response to electrical field stimulation when compared with smooth and skeletal muscle, whose responses were both significantly reduced. This phenomenon could not be explained with calcium-dependent, inhibitory, nitric oxide-releasing nerves, as the NO-synthase blocker N-nitro-L-arginine (10(-5) M to 5 x 10(-5) M) failed to induce the enhancement of sphincter contraction during electrostimulation found with calcium depletion. Still, NO-releasing nerves might play a role in sphincteric relaxation because sodium nitroprusside (10(-5) M) induced a significant relaxation of the urethral sphincter precontracted with 80 mM potassium. The potential to weaken sphincteric closure with drugs, exemplified by the results obtained in response to prazosin and cromakalim, would represent a therapeutic advance in the patient with neurogenic bladder dysfunction.

Amino Acid Oxidoreductases↗
PubMed1994

Structure and dynamics of the active site gorge of acetylcholinesterase: synergistic use of molecular dynamics simulation and X-ray crystallography.

The active site of acetylcholinesterase (AChE) from Torpedo californica is located 20 A from the enzyme surface at the bottom of a narrow gorge. To understand the role of this gorge in the function of AChE, we have studied simulations of its molecular dynamics. When simulations were conducted with pure water filling the gorge, residues in the vicinity of the active site deviated quickly and markedly from the crystal structure. Further study of the original crystallographic data suggests that a bis-quaternary decamethonium (DECA) ion, acquired during enzyme purification, residues in the gorge. There is additional electron density within the gorge that may represent small bound cations. When DECA and 2 cations are placed within the gorge, the simulation and the crystal structure are dramatically reconciled. The small cations, more so than DECA, appear to stabilize part of the gorge wall through electrostatic interactions. This part of the gorge wall is relatively thin and may regulate substrate, product, and water movement through the active site.

Acetylcholinesterase↗
PubMed1993

Decamethonium is a partial agonist at the nicotinic acetylcholine receptor.

The efficacy of decamethonium as an agonist at the nicotinic acetylcholine receptor has never been determined. Here, we demonstrate how patch clamp recording during rapid perfusion of agonists to outside-out patches from BC3H-1 cells can be used to provide an unambiguous estimate of the efficacy of decamethonium. First, we obtain the decamethonium concentration-response relationship between 10 and 1,000 microM decamethonium. The maximum channel open probability is small (< 0.02) and occurs at about 100 microM. This suggests two alternative explanations: decamethonium is a poor agonist or decamethonium is an efficacious agonist but a potent channel blocker. To distinguish between these alternatives, we perfuse mixtures of decamethonium and acetylcholine to generate acetylcholine concentration-response curves in the presence of 30, 100, and 1,000 microM decamethonium. We use a model for activation and block of the acetylcholine receptor by both agonists to fit these data and determine the binding affinity, efficacy, and blocking affinity of decamethonium. We conclude that the efficacy of decamethonium is low, 0.016. Decamethonium is a true partial agonist.

Acetylcholine↗
PubMed1976

Cholinomimetic teratogens. III. Interaction with amino acids known as neurotransmitters.

The amino acids gamma-aminobutyric acid, taurocholate, guanidine, glycine, and beta-alanine, known to have putative functions as neurotransmitters, when given as supplement to carbachol or decamethonium, greatly reduced the incidence of malformations produced in chicken embryos by these depolarizing cholinomimetic teratogens. In combination with the nondepolarizing teratogens neostigmine and pyridostigmine similarly beneficial effects occurred only by supplementation with gamma-aminobutyric acid.

Alanine↗
PubMed1978

Cholinomimetic teratogens. VI. The interaction of cholinomimetic teratogens with the antimalarial drugs chloroquine and chlorguanide.

A typical syndrome of short and crooked neck together with muscular hytoplasia of the legs occurs with low incidence in chicken embryos following injection into the egg at 24 hours of incubation of the antimalarial drug chloroquine; but treatment at later stages does not have similar effects. When, however chloroquine was used in addition to carbachol or neostigmine at 96 hours of incubation the malformations caused by the two cholinomimetic compounds, i.e., carbachol and neostigmine, occurred with greatly increased frequency and tended also to be exaggerated in expression. Chlorguanide, another antimalarial drug, when used as additive, reduced the teratogenic effects of such compounds as decamethonium and neostigmine. It appears that the neuromuscular pathways to teratogenicity are for carbachol and neostigmine and for chloroquine clearly related, if at different levels of expressivity.

Abnormalities, Drug-Induced↗
PubMed1981

Neuromuscular blocking agents and axial teratogenesis in the avian embryo. Can axial morphogenetic disorders by explained by pharmacological action upon muscle tissue?

A comparative qualitative and quantitative study of the embryotoxic and teratogenic activities of various chemical agents known to have neuromuscular blocking properties was done on the quail embryo. Intrinsic embryotoxic activity and teratogenicity were evaluated for each agent, and the qualitative nature of the teratogenic effects was correlated with the pharmacologic properties of the different effectors. Gross malformations (contorted posture) were found only with agents which directly (cholinergic agonists) or indirectly (cholinesterase inhibitors) favor muscle membrane depolarization, suggesting that such malformations may be due to muscle contraction following depolarization. All of the agents studied produced variable degrees of vertebral fusion, apparently due to paralysis resulting either from sustained depolarization (cholinesterase inhibitors and cholinergic agonists) or directly from cholinergic blockade (cholinergic antagonists and neurotoxins).

Abnormalities, Drug-Induced↗