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PubMed1986

Free energy coupling between H+-generating and H+-consuming pumps. Ratio between output and input forces.

The delta Gp/delta mu H ratio has been measured in mitochondria close to state 4 in the presence of various uncoupler or K+/valinomycin concentrations in media containing either 1 mM or 50 mM Pi. Care has been taken to control the factors affecting delta Gp and delta mu H which could lead to an artefactual increase of the delta Gp/delta mu H ratio above the highest accepted value for the H+/ATP stoichiometry (n = 4, synthesis + transport). In particular, to avoid overestimation of delta Gp due to inactivation of the ATPases at low delta mu H or to the presence of adenylate kinase, the static head state was approached from the side of net ATP synthesis and delta Gp was measured in a state close to static head but still maintaining a residual rate of aerobic phosphorylation. For each concentration of uncoupler or K+, the Pi concentration and/or the adenylate energy charge (EC) as a function of time have been measured as indicators of net ATP synthesis. Only the values of delta Gp measured during a decrease in Pi concentration and/or an increase in EC have been considered to be meaningful for calculations of delta Gp/delta mu H ratios. Both uncouplers and K+ transport cause a marked depression of delta mu H and a parallel depression of the rate of ATP synthesis. However the low rate of ATP synthesis taking place under conditions of low delta mu H eventually results, especially at high Pi concentrations, in a relatively large delta Gp. The delta Gp/delta mu H ratios obtained at the lower delta mu H values exceed 4 and approach 6. Although slightly higher delta Gp/delta mu H ratios are obtained with valinomycin-treated than with uncoupler-treated mitochondria, the pattern of the rise of the force ratio as delta mu H decreases is similar in both cases. An increase of the delta Gp/delta mu H ratio above 4, the maximal accepted H+/ATP stoichiometry is thermodynamically incompatible with the delocalized protonic coupling model.

Adenosine Triphosphate↗

PubMed2001

Potentiation and inhibition of Ca(2+) release-activated Ca(2+) channels by 2-aminoethyldiphenyl borate (2-APB) occurs independently of IP(3) receptors.

1. The effects of the IP(3)-receptor antagonist 2-aminoethyldiphenyl borate (2-APB) on the Ca(2+) release-activated Ca(2+) current (I(CRAC)) in Jurkat human T cells, DT40 chicken B cells and rat basophilic leukaemia (RBL) cells were examined. 2. 2-APB elicited both stimulatory and inhibitory effects on Ca(2+) influx through CRAC channels. At concentrations of 1-5 microM, 2-APB enhanced Ca(2+) entry in intact cells and increased I(CRAC) amplitude by up to fivefold. At levels > or = 10 microM, 2-APB caused a transient enhancement of I(CRAC) followed by inhibition. 3. 2-APB altered the kinetics of fast Ca(2+)-dependent inactivation of I(CRAC). At concentrations of 1-5 microM, 2-APB increased the rate of fast inactivation. In contrast, 2-APB at higher concentrations (> or = 10 microM) reduced or completely blocked inactivation. 4. 2-APB inhibited Ca(2+) efflux from mitochondria. 5. 2-APB inhibited I(CRAC) more potently when applied extracellularly than intracellularly. Furthermore, increased protonation of 2-APB at low pH did not affect potentiation or inhibition. Thus, 2-APB may have an extracellular site of action. 6. Neither I(CRAC) activation by passive store depletion nor the effects of 2-APB were altered by intracellular dialysis with 500 microg ml(-1) heparin. 7. I(CRAC) is present in wild-type as well as mutant DT40 B cells lacking all three IP(3) receptor isoforms. 2-APB also potentiates and inhibits I(CRAC) in both cell types, indicating that 2-APB exerts its effects independently of IP(3) receptors. 8. Our results show that CRAC channel activation does not require physical interaction with IP(3) receptors as proposed in the conformational coupling model. Potentiation of I(CRAC) by 2-APB may be a useful diagnostic feature for positive identification of putative CRAC channel genes, and provides a novel tool for exploring the physiological functions of store-operated channels.

Animals↗

PubMed1989

Quantum yields for laser photocyclization of bilirubin in the presence of human serum albumin. Dependence of quantum yield on excitation wavelength.

The quantum yield for laser photocyclization of bilirubin to lumirubin in the presence of human serum albumin (phi LR) was measured at five monochromatic excitation wavelengths in the range 450-530 nm. Solutions used were optically thin throughout the wavelength range and precautions were taken to exclude contributions from photocyclization of bilirubin XIII alpha impurities. The values obtained (7.2-18 x 10(-4] were lower than those previously reported and showed the following wavelength dependence: 457.9 less than 488.0 less than 501.7 less than 514.5 approximately equal to 528.7. However, the rate of lumirubin formation, normalized to constant fluence, decreased with wavelength over the same wavelength range and no evidence was found that photoisomerization of bilirubin to lumirubin is faster with green (514.5 or 528.7 nm) than with blue (457.9 or 488.0 nm) light. The stereoselectivity of the configurational isomerization of bilirubin to 4Z,15E and 4E,15Z isomers also was studied. This reaction became less regioselective for the 4Z,15E isomer with increasing wavelength. The observed wavelength dependence of phi LR and of the [4E,15Z]: [4Z,15E] ratio at photoequilibrium are consistent with an exciton coupling model in which intramolecular energy transfer can occur between the two pyrromethenone chromophores of the bilirubin molecule in the excited state. Relative rates of lumirubin formation in vivo at different excitation wavelengths and constant fluence were estimated for different optical thicknesses and for different skin thicknesses. These estimates suggest that the recently reported clinical equivalence of blue and green phototherapy lights probably reflects the marked variation of skin transmittance with wavelength more than wavelength-dependent photochemistry. The calculations also indicated that the optimal wavelength for phototherapy is probably on the long wavelength side of the bilirubin absorption maximum.

Bilirubin↗

PubMed2003

Mechanisms of H+ modulation of glycinergic response in rat sacral dorsal commissural neurons.

Many ionotropic receptors are modulated by extracellular H+. So far, few studies have directly addressed the role of such modulation at synapses. In the present study, we investigated the effects of changes in extracellular pH on glycinergic miniature inhibitory postsynaptic currents (mIPSCs) as well as glycine-evoked currents (IGly) in mechanically dissociated spinal neurons with native synaptic boutons preserved. H+ modulated both the mIPSCs and IGly biphasically, although it activated an amiloride-sensitive inward current by itself. Decreasing extracellular pH reversibly inhibited the amplitude of the mIPSCs and IGly, while increasing external pH reversibly potentiated these parameters. Blockade of acid-sensing ion channels (ASICs) with amiloride, the selective antagonist of ASICs, or decreasing intracellular pH did not alter the modulatory effect of H+ on either mIPSCs or IGly. H+ shifted the EC50 of the glycine concentration-response curve from 49.3 +/- 5.7 microM at external pH 7.4 to 131.5 +/- 8.1 microM at pH 5.5, without altering the Cl- selectivity of the glycine receptor (GlyR), the Hill coefficient and the maximal IGly, suggesting a competitive inhibition of IGly by H+. Both Zn2+ and H+ inhibited IGly. However, H+ induced no further inhibition of IGly in the presence of a saturating concentration of Zn2+. In addition, H+ significantly affected the kinetics of glycinergic mIPSCs and IGly. It is proposed that H+ and/or Zn2+ compete with glycine binding and inhibit the amplitude of glycinergic mIPSCs and IGly. Moreover, binding of H+ induces a global conformational change in GlyR, which closes the GlyR Cl- channel and results in the acceleration of the seeming desensitization of IGly as well as speeding up the decay time constant of glycinergic mIPSCs. However, the deprotonation rate is faster than the unbinding rate of glycine from the GlyR, leading to reactivation of the undesensitized GlyR after washout of agonist and the appearance of a rebound IGly. H+ also modulated the glycine cotransmitter, GABA-activated current (IGABA). Taken together, the results support a "conformational coupling" model for H+ modulation of the GlyR and suggest that H+ may act as a novel modulator for inhibitory neurotransmission in the mammalian spinal cord.

2-Amino-5-phosphonovalerate↗

PubMed2003

The application of smart structures toward feedback suppression in amplified acoustic guitars.

Smart structures technology can be applied to amplified acoustic guitars to prevent instability resulting from acoustic feedback. This work presents a coupled model of the guitar dynamics and the acoustic feedback mechanism, and explains how a simple control loop using a piezoelectric ceramic actuator can be used to reduce the effects of acoustic feedback. In addition to model simulations, experimental results using a real system and a simple controller are presented. The results show that a significantly higher (7 dB) guitar output can be achieved before instability, without detrimentally affecting the amplified and unamplified guitar response.

Journal Article↗

PubMed1998

Viscosity of oceanic asthenosphere inferred from remote triggering of earthquakes

A sequence of large interplate earthquakes from 1952 to 1965 along the Aleutian arc and Kurile-Kamchatka trench released accumulated stresses along nearly the entire northern portion of the Pacific Plate boundary. The postseismic stress evolution across the northern Pacific and Arctic basins, calculated from a viscoelastic coupling model with an asthenospheric viscosity of 5 x 10(17) pascal seconds, is consistent with triggering of oceanic intraplate earthquakes, temporal patterns in seismicity at remote plate boundaries, and space-based geodetic measurements of anomalous velocity over an area 7000 by 7000 kilometers square during the 30-year period after the sequence.

Journal Article↗

PubMed2004

Rusty, jammed, and well-oiled hinges: Mutations affecting the interdomain region of FliG, a rotor element of the Escherichia coli flagellar motor.

The FliG protein is a central component of the bacterial flagellar motor. It is one of the first proteins added during assembly of the flagellar basal body, and there are 26 copies per motor. FliG interacts directly with the Mot protein complex of the stator to generate torque, and it is a crucial player in switching the direction of flagellar rotation from clockwise (CW) to counterclockwise and vice versa. A primarily helical linker joins the N-terminal assembly domain of FliG, which is firmly attached to the FliF protein of the MS ring of the basal body, to the motility domain that interacts with MotA/MotB. We report here the results of a mutagenic analysis focused on what has been called the hinge region of the linker. Residue substitutions in this region generate a diversity of phenotypes, including motors that are strongly CW biased, infrequent switchers, rapid switchers, and transiently or permanently paused. Isolation of these mutants was facilitated by a "sensitizing" mutation (E232G) outside of the hinge region that was accidentally introduced during cloning of the chromosomal fliG gene into our vector plasmid. This mutation partially interferes with flagellar assembly and accentuates the defects associated with mutations that by themselves have little phenotypic consequence. The effects of these mutations are analyzed in the context of a conformational-coupling model for motor switching and with respect to the structure of the C-terminal 70% of FliG from Thermotoga maritima.

Amino Acid Sequence↗

PubMed1989

Characterization of ion movements and their relationship to muscarinic receptor binding and excitation-contraction coupling in guinea pig ileal longitudinal smooth muscle.

The relationship between ion movements (sodium uptake and potassium release) and agonist-induced contractile responses or muscarinic receptor binding was investigated in the guinea pig ileal longitudinal muscle (GPLM). Sodium uptake and potassium release were agonist-dependent, concentration-dependent, and stereoselective, with the following rank order of maximum ion movement: muscarinic agonists greater than histamine greater than substance P = serotonin. Potassium depolarization did not initiate sodium uptake or potassium release. Sodium uptake was rapid and monophasic, preceding potassium release which was biphasic in nature. Full muscarinic agonists produced equal maximal increases in sodium uptake, while maximal potassium release varied for all muscarinic agonists and in addition differed from sodium uptake in the following ways: time course, stereoselectivity, sensitivity to calcium antagonists, modulation by the guanylyl nucleotide derivative, 5'-guanylylimidodiphosphate (Gpp(NH)p), and inhibition by muscarinic receptor blockade with benzilylcholine mustard. The calcium ionophores A23187 and ionomycin (SQ23377) did not produce any sodium uptake; A23187 but not ionomycin produced potassium release comparable to that evoked by muscarinic agonists. Ion movement in response to combinations of agonists were not additive. Muscarinic agonist binding as measured by competition for [3H]quinuclidinyl benzilate ([3H]QNB) binding, was best described by multiple sites and was regulated by Gpp(NH)p. Excellent correlations were observed between the dissociation constants for binding and sodium uptake, potassium release, and contraction. The best correlations were those between the pharmacologic responses and the high affinity binding site in the absence, and the low affinity site in the presence, of Gpp(NH)p, respectively. Furthermore, the potencies of muscarinic agonists to evoke ion movements and to inhibit [3H]QNB binding were similar, and from one to two orders of magnitude less than those for contraction. It is suggested that contraction and potassium release were mediated by the high affinity, and sodium uptake by the low and average affinity muscarinic agonist binding sites, respectively. These findings suggest an agonist-activated receptor-effector coupling model in GPLM that leads to the activation of sodium uptake, potassium release, and subsequently, contraction.

Animals↗

PubMed1993

Acid and base effects on avian osteoclast activity.

Osteoclasts generate a massive acid flux to mobilize bone calcium. Local extracellular acidification by polarized vacuolar-type H(+)-ATPase, balanced by contralateral HCO3-(-)Cl- exchange to maintain physiological intracellular pH, is theorized to drive this process. It follows that extracellular pH, PCO2, or HCO3- concentration ([HCO3-]) should impact bone matrix dissolution. However, the effects on bone resorption of the concentrations of these ions or their transmembrane gradients are unknown. Furthermore, because bone management is a vital process, regulatory feedback may minimize such effects. Thus a complex relationship between bone resorption and pH, PCO2, and [HCO3-] is expected but requires experimental determination. We measured bone resorption by isolated avian osteoclasts while varying these parameters across the physiological range. Bone degradation increased 50% from pH 7.3 to 6.7, whether achieved by changing [HCO3-] (2.3-38 mM) at constant HCO3- or PCO2 (15-190 mmHg) at constant [HCO3-]. However, at constant pH, changing PCO2 and [HCO3-] within physiological limits did not affect bone resorption. In contrast, total HCO3- removal at pH 7.4 reduced bone degradation by rat or avian osteoclasts substantially, confirming that normal acid secretion requires HCO3-. These observations support a model coupling osteoclastic bone resorption to proton and HCO3- transport but indicate that [HCO3-] is not rate limiting under physiological conditions. Extracellular pH changes affect osteoclastic bone resorption measurably, but not dramatically, at physiological [HCO3-].

Acid-Base Equilibrium↗

PubMed1993

Ratio of ryanodine to dihydropyridine receptors in cardiac and skeletal muscle and implications for E-C coupling.

We measured dihydropyridine receptor (DHPR) and ryanodine receptor (RYR) density in isolated ventricular myocytes from rabbits, rats, ferrets, and guinea pigs and also from rabbit ventricular homogenate, skeletal muscle homogenate, and isolated triads. In skeletal muscle homogenate and triads the RYR/DHPR ratio was 0.7 and 0.52, respectively. This stoichiometry is reasonably consistent with excitation-contraction (E-C) coupling models in skeletal muscle where the DHPR molecule itself may transmit the signal for Ca release to the sarcoplasmic reticulum (SR) and with the molecular arrangement proposed for toadfish swimbladder from ultrastructural studies by B. A. Block, T. Imagawa, K. P. Campbell, and C. Franzini-Armstrong. (J. Cell Biol. 107: 2587-2600, 1988). That is, there could be approximately two RYR for each four DHPR or two RYR feet per DHPR tetrad in an organized array (assuming 1 high-affinity RYR/foot and 4 DHPR/tetrad). The fraction of rabbit ventricular protein that is cardiac myocyte protein was also estimated (< or = 55-62%), assuming that RYR and DHPR are useful but not exclusive markers for myocytes in the ventricle. In cardiac myocytes the RYR/DHPR was much higher than in skeletal muscle and varied among different mammalian myocytes. The RYR/DHPR ratios were 3.7 in rabbit, 4.3 in guinea pig, 7.3 in rat, and 10.2 in ferret myocytes. In contrast to skeletal muscle, these results indicate that there are many more RYR feet per DHPR in cardiac muscle, and this ratio depends on species (i.e., 4-10 times and would be 4 times higher still per putative DHPR tetrad if that structure exists in mammalian heart).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Coupling calcium binding to troponin C and cross-bridge cycling in skinned cardiac cells.

This study examines the coupling of calcium binding to troponin with the force developed by the cross bridges in the skinned cardiac muscle. It emphasizes the key role of the troponin complex in regulating cross-bridge cycling and defines four distinct states of the troponin complex in the single-overlap region. These include a "loose-coupling" state, wherein cross bridges can exist in the strong conformation without having calcium bound to the neighbor troponin C. Published simultaneous measurements of the force and the bound calcium are used to calculate the apparent calcium binding coefficients. The force-length relationships at different free calcium concentrations are used to evaluate the cooperative mechanism. The dependence of the affinity of troponin for calcium on the number of force-generating cross bridges is the dominant cooperative mechanism. The proposed loose-coupling model, with a positive feedback of force on calcium binding, describes the role of calcium in force regulation and the force-length relationship in skinned cardiac muscle. The ability to simulate the rate of force development is demonstrated.

Animals↗

PubMed1993

On the nature of the circadian clock in mammals.

The evidence for the essential role of the suprachiasmatic nucleus (SCN) for the generation and maintenance of circadian rhythms in mammals is briefly reviewed. The pharmacology of the phase-response curve is considered and a new circadian measure, the phase-dose-response surface (PDRS), is introduced. The role of neurotransmission, ion fluxes, and non-neuronal cellular elements in the generation and maintenance of circadian rhythmicity is considered. Cell culture of the SCN is proposed as a tool for the functional analysis of clock mechanism. The critical contribution of coupling and synchronization of clock elements is reviewed in the context of the explicit predictions generated by a strong coupling model of the circadian clock. Finally, the nature of the circadian output signal is analyzed from a phylogenetic viewpoint.

Animals↗

PubMed1995

Coordination in the crayfish swimmeret system: differential excitation causes changes in intersegmental phase.

1. Gradients of excitation in the swimmeret system were created by applying either pilocarpine or carbachol to selected ganglia in isolated abdominal nerve cords. The state of the system was monitored in each segment with extracellular electrodes on nerves that innervated swimmerets. In preparations that were quiescent before drugs were applied, these cholinergic agonists elicited well-coordinated swimmeret motor patterns from the entire system, including ganglia that were not directly treated with pilocarpine or carbachol. 2. The periods of these patterns depended on the number of ganglia that were directly excited. As this number increased, period decreased. When the same numbers of ganglia were excited by direct application of a drug, the mean period of the swimmeret activity elicited by pilocarpine was greater than that elicited by carbachol. 3. Selective excitation of anterior or posterior ganglia caused significant changes in intersegmental phase at the boundary between excited and nonexcited regions of the nerve cord. When only anterior ganglia were excited directly, the phases of their power-stroke activity relative to the most posterior ganglion were advanced. When only posterior ganglia were excited directly, the phases of power-stroke activity in more anterior ganglia were retarded. Neither pilocarpine nor carbachol caused a complete reversal of the normal phase relations of the swimmeret motor patterns. 4. These results are consistent with an asymmetric-coupling model of the intersegmental coordinating circuit of the swimmeret system but contradict an alternative excitability-gradient model.

Abdomen↗

PubMed2006

Human kallikrein 8 protease confers a favorable clinical outcome in non-small cell lung cancer by suppressing tumor cell invasiveness.

The human kallikrein 8 (KLK8) gene, a member of the human tissue kallikrein gene family, encodes a serine protease. The KLK8 protein (hK8) is known to be a favorable prognostic marker in ovarian cancer, but the biological basis of this is not understood. We found that overexpressing the KLK8 gene in highly invasive lung cancer cell lines suppresses their invasiveness. This role in invasiveness was further confirmed by the fact that inhibition of endogenous KLK8 expression with a specific short hairpin RNA reduced cancer cell invasiveness. In situ degradation and cell adhesion assays showed that proteins produced from KLK8 splice variants modify the extracellular microenvironment by cleaving fibronectin. DNA microarray experiments and staining of cells for actin filaments revealed that the degradation of fibronectin by hK8 suppresses integrin signaling and retards cancer cell motility by inhibiting actin polymerization. In addition, studies in a mouse model coupled with the detection of circulating tumor cells by quantitative PCR for the human Alu sequence showed that KLK8 suppresses tumor growth and invasion in vivo. Finally, studies of clinical specimens from patients with non-small cell lung cancer showed that the time to postoperative recurrence was longer for early-stage patients (stages I and II) with high KLK8 expression (mean, 49.9 months) than for patients with low KLK8 expression (mean, 22.9 months). Collectively, these findings show that KLK8 expression confers a favorable clinical outcome in non-small cell lung cancer by suppressing tumor cell invasiveness.

Base Sequence↗

PubMed1985

Postextrasystolic potentiation of the isolated canine left ventricle. Relationship to mechanical restitution.

We established, for the isolated, isovolumically beating canine left ventricle, a comprehensive description of postextrasystolic contractile strength (dP/dtmax) as a function of extrasystolic and postextrasystolic stimulus intervals. In contrast to previous studies of postextrasystolic beats in in situ hearts, these isolated ventricles contracted isovolumically so that dP/dtmax was not affected by fluctuations in preload and afterload and was therefore considered to be a reliable index of intrinsic contractility. With the interval preceding extrasystoles constant, postextrasystolic contractile strength increased monoexponentially to a plateau as the interval preceding postextrasystoles lengthened, with a mean time constant (+/- SD) of 182 +/- 44 msec (n = 53). The onset of this increase in postextrasystolic contractile strength coincided with repolarization of the extrasystolic action potential. With the interval preceding postextrasystoles held constant and long (1200 msec), postextrasystolic contractile strength decreased according to a monoexponential function as the interval preceding extrasystoles lengthened [mean time constant (+/- SD) of 176 +/- 18 msec (n = 10)]. These phenomena could be quantitatively summarized by a single equation description of postextrasystolic contractile strength which involved monoexponential functions with one time constant. The mathematical form of this description led us to a simple interpretation of these phenomena in terms of currently proposed excitation-contraction coupling models of the heart.

Animals↗

PubMed2004

Differences of globin transgene expression in stably transfected cell lines and transgenic mice.

Previous studies demonstrated that DNase I hypersensitive site -40 (HS-40) of the alpha-globin locus is capable of greatly enhancing expression of a hybrid beta/gamma-globin transcriptional unit in plasmid-transfected murine erythroleukemia (MEL) cells. However, as reported here, this same gamma-globin gene expression cassette was only transcribed at trace amounts in erythroid cells of transgenic mice. This lack of expression was not directly attributable to the beta/gamma-globin transcriptional unit, since this same unit linked to a composite beta-globin locus control region was expressed at high levels in transgenic mice. This lack of expression was also not directly attributable to chromosomal position effects, since addition of chromatin insulators failed to increase the frequency of expression. DNase I hypersensitivity and chromatin immunoprecipitation assays demonstrated that the lack of expression was correlated with a closed chromatin structure. We hypothesize that transgenes undergo dynamic changes in chromatin conformation following chromosomal integration and that the discrepant results reported here can be attributed to the relatively high level of chromatin remodeling that occurs in the transgenic mouse model, coupled with the relative inability of the HS-40 element to maintain an open chromatin state under such conditions.

Animals↗

PubMed1986

Shape control in the human red cell.

When the human red cell consumes its ATP, the cell loses its discoid character in favour of a spiculated and eventually a spherical form. This discocyte-echinocyte transformation parallels both degradation of phosphatidylinositol 4,5-bisphosphate and phosphatidic acid but not dephosphorylation of cytoskeletal proteins. Dephosphorylation of both spectrin and band 3 lags behind metabolic crenation. Exogenous vanadate accelerates both shape changes and lipid dephosphorylation in a parallel manner during metabolic depletion. In contrast to its effect on lipids, vanadate reduces the rate of protein dephosphorylation. These observations strongly support a shape control mechanism in the red cell, based on phosphoinositide metabolism and compatible with a bilayer-couple model.

Adenosine Triphosphate↗

PubMed1991

Kinetic evaluation of pharmacological effects based on allosteric coupling of the benzodiazepine/gamma-aminobutyric acidA receptor in the brain.

A mathematical allosteric coupling model has been proposed to describe the process by which binding to the benzodiazepine/gamma-aminobutyric acid (GABA) receptor complex initiates a biological response. The model states that the first receptors (benzodiazepine receptors) can diffuse independently in the plane of the membrane and reversibly associate with the second receptors (GABA receptors) to regulate their activity (induction of increased chloride ion flux due to the opening of the chloride ion channel). The ratio of agonist-bound to total GABA receptor density was defined to be directly proportional to the biological response in the model. The analysis makes the following assumptions: i) the binding affinity of agonists (muscimol or benzodiazepine) to the benzodiazepine receptor/GABA receptor complex is much greater than that to each receptor alone; ii) the double receptor-single agonist (benzodiazepine, muscimol or GABA) ternary complex binds to the other agonist with a high binding affinity as compared with that of each agonist to an agonist-free receptor complex; iii) benzodiazepine receptor-GABA receptor interaction is enhanced in the presence of each agonist; iv) the GABA receptor is desensitized after the binding of GABA agonist (GABA or muscimol) to the receptor. The modeling exercise shows that the benzodiazepine concentration required for half-maximal biological response is lower than that required for half-maximal receptor binding. In the case of the GABA agonist, a linear relationship between receptor occupancy and biological response was observed. The degree of discrepancy between the two profiles (receptor occupancy and biological response) concerning benzodiazepine concentration dependency and time dependency increased with a decrease in the dissociation constants based on the benzodiazepine receptor-GABA receptor interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗