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At least 649 records · Page 36Linked to original sources
PubMed1993

Essential role of myosin S-2 region in muscle contraction.

We studied the contraction characteristics and Mg-ATPase activity of glycerinated rabbit psoas muscle fibers in the presence and absence of polyclonal antibody directed against the subfragment-2 (S-2) region of myosin, to give information about the role of myosin hinge region in muscle contraction. The antibody was kindly supplied to us from Professor Harrington's laboratory. The antibody-induced decrease of Ca(2+)-activated isometric force development was always accompanied by a parallel decrease of muscle fiber stiffness, so that the stiffness versus force relation remained the same by the antibody treatment. Force-velocity curves, obtained by applying ramp decreases in load from steady isometric force to zero, indicated that the antibody had no effect on the maximum shortening velocity and the shape of the force-velocity curve. Simultaneous measurements of Mg-ATPase activity and Ca(2+)-activated isometric force showed that Mg-ATPase activity of the fibers remained unchanged despite the antibody-induced decrease of isometric force even to zero. These results indicate that, if the antibody attaches to the S-2 region of myosin molecules, their heads still hydrolyze ATP without contributing to both muscle force generation and muscle fiber stiffness.

Animals↗
PubMed2004

Correlation between mechanical and enzymatic events in contracting skeletal muscle fiber.

The conventional hypothesis of muscle contraction postulates that the interaction between actin and myosin involves tight coupling between the power stroke and hydrolysis of ATP. However, some in vitro experiments suggested that hydrolysis of a single molecule of ATP caused multiple mechanical cycles. To test whether the tight coupling is present in contracting muscle, we simultaneously followed mechanical and enzymatic events in a small population of cross-bridges of glycerinated rabbit psoas fibers. Such small population behaves as a single cross-bridge when muscle contraction is initiated by a sudden release of caged ATP. Mechanical events were measured by changes of orientation of probes bound to the regulatory domain of myosin. Enzymatic events were simultaneously measured from the same cross-bridge population by the release of fluorescent ADP from the active site. If the conventional view were true, ADP desorption would occur simultaneously with dissociation of cross-bridges from thin filaments and would be followed by cross-bridge rebinding to thin filaments. Such sequence of events was indeed observed in contracting muscle fibers, suggesting that mechanical and enzymatic events are tightly coupled in vivo.

Adenosine Diphosphate↗
PubMed2026

Signaling mechanisms of vasopressin/oxytocin-type neuropeptide-induced muscle contraction in the sea cucumber Apostichopus japonicus.

The myoregulatory action of vasopressin/oxytocin (VP/OT)-type neuropeptides is evolutionarily conserved across Bilateria. In vertebrates, the signaling cascades involved have been comprehensively characterized in several muscle types, including uterine and gastrointestinal smooth muscles. VP/OT-type neuropeptide-induced muscle contraction or relaxation has been reported in a variety of invertebrates, but the downstream signaling pathways responsible for these effects have yet to be elucidated. Here, using heterologous cell systems and in vitro pharmacological experiments, we investigated the signaling pathways underlying VP/OT-type neuropeptide (holotocin) induced contraction of the longitudinal muscle of the body wall (LMBW) in the sea cucumber Apostichopus japonicus (phylum Echinodermata), a deuterostome invertebrate. Holotocin-induced contraction of the LMBW comprised two distinct phases: an initial rapid phasic contraction followed by a sustained tonic contraction. Pharmacological experiments revealed that upon binding to its receptor AjHOR, holotocin activates a Gαq-dependent pathway, leading to phospholipase C (PLC) activation and subsequent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers Ca2+ release from intracellular Ca2+ stores via IP₃ receptors (IP3R), but depletion of intracellular Ca2+ does not activate store-operated Ca2+ entry (SOCE). DAG activates protein kinase C (PKC), which may modulate the activity of ion channels in the plasma membrane, resulting in membrane depolarization, opening of voltage-gated Ca2+ channels (VGCCs), and subsequent influx of extracellular Ca2+. Overall, this study reveals similarities and differences in the signaling pathways mediating smooth muscle contraction in invertebrates and vertebrates, providing new insights into the evolution of these mechanisms across the Bilateria.

Ca(2+)↗
PubMed2001

Arachidonic acid-induced Ca2+ sensitization of smooth muscle contraction through activation of Rho-kinase.

Arachidonic acid activates isolated Rho-kinase and contracts permeabilized smooth muscle fibres. Various assays were carried out to examine the mechanism of this activation. Native Rho-kinase was activated 5-6 times by arachidonic acid but an N-terminal, constitutively-active fragment of Rho-kinase, expressed as a glutathione-S-transferase (GST) fusion protein and including the catalytic subunit (GST-Rho-kinase-CAT), was not. GST-Rho-kinase-CAT was inhibited by a C-terminal fragment of Rho-kinase and arachidonic acid removed this inhibition. These results suggest that the C-terminal part of Rho-kinase, containing the RhoA binding site and the pleckstrin homology domain, acts as an autoinhibitor. It is suggested further that activation by arachidonic acid is due to its binding to the autoinhibitory region and subsequent release from the catalytic site. Arachidonic acid, at concentrations greater than 30 microM, increases force in alpha-toxin-permeabilized femoral artery but not in Triton X-100-skinned fibres. The content of Rho-kinase in the latter was lower than in alpha-toxin-treated or intact fibres. The arachidonic acid-induced contraction was not observed at a pCa above 8.0 and was inhibited by Y-27632 and wortmannin, inhibitors of Rho-kinase and myosin light-chain kinase (MLCK), respectively. The activation of Rho-kinase and subsequent phosphorylation of the myosin phosphatase target subunit inhibits myosin phosphatase and increases myosin phosphorylation.

Amides↗
PubMed1991

Hsp27 is a mediator of sustained smooth muscle contraction in response to bombesin.

We have identified the low MW 27 kD heat shock protein as a major phosphoprotein constituent of smooth muscle and have investigated its potential role in agonist induced smooth muscle contraction. The neuropeptides bombesin and substance P, which are present in neurons of the anorectal region, induce contraction of isolated smooth muscle cells from this region by activating different intracellular pathways. Substance P-induced contraction is 1,4,5-inositol trisphosphate (IP3)/calmodulin dependent, while contraction induced by bombesin is mediated by a protein kinase C (PKC)-dependent pathway. The sustained contraction induced by bombesin or exogenous PKC was blocked by preincubation of cells with monoclonal antibodies to hsp27, while the transient contraction induced by substance P or IP3 was unaffected by the antibodies. Preincubation with isotype matched control antibodies had no inhibitory effect on contraction induced in response to the agents used. These data support a novel role for hsp27 in the non calmodulin mediated sustained contraction induced by bombesin or PKC.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Reserpine-induced post-receptor reduction in muscarinic-mediated airway smooth muscle contraction.

Radioligand binding was conducted on airways of the rat and human, surgically subdivided into trachea, lung airways, and parenchyma. 3H-QNB bound uniformly to receptors in separate sections of the rat and human airway. Receptor densities generally were ranked: lung airways greater than trachea greater than parenchyma. Receptor subtypes were identified mostly by pirenzepine displacement of bound 3H-QNB. The rat trachea, and rat and human lung airways had a uniformly low affinity for pirenzepine while rat and human parenchyma demonstrated both high and low affinity pirenzepine binding. Inhibition of methacholine-stimulated smooth muscle contraction by the M1 receptor antagonist, pirenzepine, and M2 receptor antagonist, gallamine, was studied in rat trachea and bronchus in vitro. Schild plot pA2 values were compatible with low potency antagonism, thereby favoring the presence of M3 receptors at these smooth muscle sites. Reserpine treatment of rats (0.5 mg kg-1 day-1 for 7 days) produced a decrease in peak tension in response to methacholine without changing the muscarinic receptor character (Kd 3H-QNB), population density (Bmax in fmol mg-1 protein), or function (methacholine EC50). These results indicate that muscarinic receptor heterogeneity exists in the airway of both laboratory rat and man. While the muscarinic receptor subserving airway smooth muscle contraction appears to be the M3 subtype, decreased contractile responses to methacholine by trachea and bronchus from reserpine-treated rats were receptor independent.

Animals↗
PubMed1995

Resolution of three structural states of spin-labeled myosin in contracting muscle.

We have used electron paramagnetic resonance (EPR) spectroscopy to detect ATP- and calcium-induced changes in the structure of spin-labeled myosin heads in glycerinated rabbit psoas muscle fibers in key physiological states. The probe was a nitroxide iodoacetamide derivative attached selectively to myosin SH1 (Cys 707), the conventional EPR spectra of which have been shown to resolve several conformational states of the myosin ATPase cycle, on the basis of nanosecond rotational motion within the protein. Spectra were acquired in rigor and during the steady-state phases of relaxation and isometric contraction. Spectral components corresponding to specific conformational states and biochemical intermediates were detected and assigned by reference to EPR spectra of trapped kinetic intermediates. In the absence of ATP, all of the myosin heads were rigidly attached to the thin filament, and only a single conformation was detected, in which there was no sub-microsecond probe motion. In relaxation, the EPR spectrum resolved two conformations of the myosin head that are distinct from rigor. These structural states were virtually identical to those observed previously for isolated myosin and were assigned to the populations of the M*.ATP and M**.ADP.Pi states. During isometric contraction, the EPR spectrum resolves the same two conformations observed in relaxation, plus a small fraction (20-30%) of heads in the oriented actin-bound conformation that is observed in rigor. This rigor-like component is a calcium-dependent, actin-bound state that may represent force-generating cross-bridges. As the spin label is located near the nucleotide-binding pocket in a region proposed to be pivotal for large-scale force-generating structural changes in myosin, we propose that the observed spectroscopic changes indicate directly the key steps in energy transduction in the molecular motor of contracting muscle.

Adenosine Triphosphate↗
PubMed1975

[Components of cholinergic excitation coupling with smooth muscle contraction in the guinea pig taenia coli].

In concentrations of 10(-9)-10(-7) g/ml acetylcholine increased the tone of the smooth muscles of the longitudinal band of the large intestine of a guinea pig, increasing the permeability of the cellular membranes for the entering flux of 45Ca2+. In concentrations of 10(-6) g/ml and over acetylcholine caused a release of the membranous calcium and in the concentrations of 10(-5)-10(-3) g/ml markedly increased the permeability of the membranes of the smooth muscle cells for the 22Na+ ions causing depolarization and an increase in the frequency of the action potentials. It is supposed that the coupling of the cholinergic stimulus with the end effect (muscle contraction) included 3 components: intensification of the entrance of Ca2+ into the smooth muscle cells, release of the membrane calcium and adhesion mechanism.

Acetylcholine↗
PubMed1998

Evidence for 5' AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport.

The intracellular signaling proteins that lead to exercise-stimulated glucose transport in skeletal muscle have not been identified, although it is clear that there are separate signaling mechanisms for exercise- and insulin-stimulated glucose transport. We have hypothesized that the 5'AMP-activated protein kinase (AMPK) functions as a signaling intermediary in exercise-stimulated glucose uptake. This hypothesis was based on recent studies showing the following: 1) muscle contraction increases AMPK activity and 2) perfusion of rat hindlimb skeletal muscles with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a compound that results in increased AMPK activity, increased insulin-stimulated glucose uptake. In the current study, isolated rat epitrochlearis muscles were treated to contract in vitro (via electrical stimulation for 10 min) and/or incubated in the absence or presence of AICAR (2 mmol/l), insulin (1 micromol/l), or wortmannin (100 nmol/l). Both contraction and AICAR significantly increased AMPK activity, while the enzyme was not activated by insulin. AICAR, contraction, and insulin all increased 3-O-methylglucose (3MG) transport by threefold to fivefold above basal. The phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin completely blocked insulin-stimulated transport, but did not inhibit AICAR- or contraction-stimulated transport. The increase in glucose transport with the combination of maximal AICAR plus maximal insulin treatments was partially additive, suggesting that these stimuli increase glucose transport by different mechanisms. In contrast, there was no additive effect on glucose transport with the combination of AICAR plus contraction. These data suggest that AICAR and contraction stimulate glucose transport by a similar insulin-independent signaling mechanism and are consistent with the hypothesis that AMPK is involved in exercise-stimulated glucose uptake.

AMP-Activated Protein Kinases↗
PubMedDate not supplied

Force transducer for measurement of muscle contraction.

Single channel force transducers, intended for measurement and evaluation curves of preconditioned fibres in muscles contracting synergistically during direct or indirect electric stimulation of isolated muscle, were designed, developed and experimentally tested. The force transducers were made up of a full Wheatstone bridge composed of four semiconductor strain gauges bonded on a specially designed cantilever. The transducers with a natural frequency 350 Hz and compliance of 0.25 micron g-1 represents a very linear dependence of the output voltage upon the load giving a sensitivity for the transducers of 0.5 mV mN-1 with a bridge excitation voltage of 5 V. The nominal range of each transducer is 0-70 mN. The system is able to record even a contraction of only a few muscle fibres, both single twitches as well as sustained tonic contractions.

Animals↗
PubMed1978

Changes in the kinetics of muscle contraction in vitamin D-depleted rats.

Using an in situ rat soleus neuromuscular preparation, changes in the muscle contraction kinetics in response to vitamine D depletion were studied. For a single isometric contraction, the time-to-peak tension (Tp) and the time-for-recovery-half-way-to-resting tension (T1/2r) were recorded. For a 150 Hz, 300 msec tetanus, the T1/2r was determined. Animals raised on high-calcium, high-phosphate, vitamin D-depleted diets showed prolongation of all parameters. Repletion of vitamin D returned Tp and T1/2r values to normal. Neither dietary calcium deficiency nor thyroparathyroidectomy produced an prolongation of Tp or T1/2r values. Therefore, based upon the experimental data, it appears that vitamin D or one of its metabolites, independent of any effect on the serum calcium or serum phosphate concentration, is necessary for normal muscle relaxation.

Animals↗
PubMed1981

Tris does not inhibit isolated vascular or intestinal smooth muscle contraction.

There are conflicting reports on the effect of tris(hydroxymethyl)aminomethane (Tris) on smooth muscle contraction. Therefore, the effect of substitution of Tris for bicarbonate in physiological saline solution on smooth muscle contractility was investigated. Tris (25 mM) increased the amplitude without changing the frequency of spontaneous contractions in rat portal vein. Tris did not inhibit either norepinephrine-induced contractions in rat portal vein and aorta or histamine-induced contractions in taenia coli. When the pH of the Tris-buffered solution was lowered from the control value of 7.4 to 7.0, spontaneous contractions in portal vein as well as agonist-induced contractions in all of the above preparations were inhibited. Tris did not inhibit contractions induced by calcium in potassium-depolarized smooth muscle preparations if the Tris-buffered solution contained sufficient amounts of sodium ion (as did bicarbonate-buffered solution). These results suggest that Tris does not inhibit contractile responses of isolated vascular and intestinal smooth muscle preparations provided that the conditions other than the buffer system (especially pH of solution) are similar to those in bicarbonate-buffered solutions.

Animals↗
PubMed1991

Calcium dependent regulation of vascular smooth muscle contraction.

The experimental results discussed from our laboratory as well as from numerous other laboratories investigating the regulation of smooth muscle contraction have, in our opinion, clearly demonstrated that a simple Ca2+ dependent switch (MLC phosphorylation) cannot completely explain all of the mechanical and energetic findings. We and others have demonstrated that stress can be developed in the complete absence of increases in MLC phosphorylation, that crossbridge cycling rate can be regulated independent of changes in MLC phosphorylation, that Ca2+ can directly influence both stress and crossbridge cycling rate, and that protein kinase C can, apparently, directly initiate the development of stress supported by a specific population of crossbridges characterized by unphosphorylated MLC, low cycling rates, and weak binding characteristics. This information combined with the wealth of material demonstrating the important function played by the Ca2+ and calmodulin dependent MLC kinase is consistent with the hypothesis that there are two Ca2+ dependent regulatory systems acting in parallel in smooth muscle. One of these is the Ca2+ dependent MLC phosphorylation-dephosphorylation system responsible for the rapid development of stress and the second is a hypothesized Ca2+ dependent system responsible for the slow development of stress as well as the maintenance of previously developed stress. This second system has a higher Ca2+ sensitivity than that for MLC phosphorylation and may be activated by protein kinase C. The total stress attained by smooth muscle is activated by protein kinase C. The total stress attained by smooth muscle is the result of these two regulatory systems acting in concert. Although we believe the available information is consistent with this hypothesis of two regulatory systems functioning in parallel, it is by no means the only possibility. Early work from our laboratory and the recent work by the Somlyos and their colleagues and Kubota et al. suggest the possibility of a regulated MLC phosphatase which might functionally alter the Ca2+ sensitivity of the contractile filaments. Kerrick and Hoar and Nishimura and van Breemen have published data which imply a role for MgADP in latchbridge kinetics. These findings, as well as the discovery of several thin filament protein components which have been proposed as regulatory units, must all be taken into account in the final answer to the question: How does Ca2+ contract smooth muscle?

Animals↗
PubMedDate not supplied

[Membrane mechanisms of activating depolarized smooth muscle contraction (guinea pig small intestine) during exposure to physiologically active compounds].

The experiments were performed on the depolarized smooth muscle of taenia coli with the use of double sucrose-gap arrangement. Muscle contractions were induced by 1) application of hystamin or bradikynin; 2) rectangular long-lasting (10--20 s) pulses of hyperpolarizing current--the strong contraction appeared in response to the switching off the current (off-response). Both the on- and off-responses to the hyperpolarizing current recorded before, during and after hystamine (or bradikynin)-induced contration were, as a rule, very similar. Treatment of smooth muscle with local anaesthetics (procaine, trimecaine, QX-572) removed hystamine- and bradikynin-induced contrations and only decreased off-responses. The analysis of the data obtained suggested the existence of the independent electrically and chemically excitable systems (channels?) OF Ca2+ ion transport in the membrane of smooth muscle cells.

Animals↗
PubMed2006

Physiological consequences of thin filament cooperativity for vertebrate striated muscle contraction: a theoretical study.

Bindings of both myosin and Ca(2+) to the thin filament of vertebrate striated muscle are known to be strongly cooperative. Here the relation between these two sources of cooperativity and their consequences for physiological properties are assessed by comparing two models, with and without Monod-type myosin-binding cooperativity. In both models a thin filament regulatory unit (RU) is in either 'off' or 'on' state, and the equilibrium between them (K (on)) is [Ca(2+)]-dependent. The calculations predict the following: (1) In both models, myosin binding stabilizes the RU in the 'on' state, causing troponin to trap Ca(2+). This stabilization in turn increases the Ca(2+)-binding cooperativity, ensuring efficient regulation to occur in a narrow [Ca(2+)] range. (2) In the cooperative model, the RU is stabilized with a relatively low myosin affinity for actin (K approximately approximately 1), while the non-cooperative model requires a much higher affinity (K approximately approximately 10) to produce the same effect. (3) The cooperative model reproduces the known effects of [Ca(2+)] on the rate of force development and shortening velocity with a low K, but again the non-cooperative model requires a higher value. (4) Because of the finite value of K (on), the thin filaments can never be fully activated by increasing [Ca(2+)], indicating that contracting muscles are under strong influence of thin-filament cooperativity even at saturating [Ca(2+)]. Interpretation of data on muscle mechanics without considering these cooperative effects could therefore lead to a substantial (10-fold) overestimate of cross-bridge binding properties.

Actin Cytoskeleton↗