Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small angle x-ray scattering has been used to investigate the structure of synaptoneurosomal (SNM) membranes from rat cerebral cortex. Electron micrographs of the preparation showed SNM with classical synaptic appositions intact, other vesicles, occasional mitochondria, and some myelin. An immunoassay for myelin basic protein placed the myelin content of normal rat SNM at less than 2% by weight of the total membrane present. X-Ray diffraction patterns showed five diffraction orders with a unit cell repeat for the membrane of 71 to 78 A at higher hydration states. At lower hydration, 11 orders appeared; the unit cell repeat was 130 A, indicating that the unit cell contained two membranes. Electron density profiles for the 130-A unit cell were determined; they clearly showed the two opposed asymmetrical membranes of the SNM vesicles. SNM membrane/buffer partition coefficients (Kp) of imidazobenzodiazepine and 1,4-dihydropyridine (DHP) calcium channel drugs were measured; Kp's for DHP drugs were approximately five times higher in rabbit light sarcoplasmic reticulum than in SNM. Ro 15-1788 and the DHP BAY K 8644 bind primarily to the outer monolayer of vesicles of intact SNM membranes. Nonspecific equilibrium binding of Ro 15-1788 occurs mainly in the upper acyl chain of the bilayer in lipid extracts of SNM membrane.
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PMID:Rat cerebral cortical synaptoneurosomal membranes. Structure and interactions with imidazobenzodiazepine and 1,4-dihydropyridine calcium channel drugs. 169 72

Ion channels permeable to barium and calcium were reconstituted from the Aplysia nervous system into phospholipid bilayers formed on the tips of patch electrodes. With asymmetrical concentrations of barium or calcium on the two sides of the bilayer, the single-channel currents reversed at the calculated barium or calcium reversal potentials, indicating that the channels were cation selective. Channels with conductances of 10, 25 and 36 pS were routinely observed. Calcium and barium were equally effective as charge carriers for the 36-pS channel, whereas magnesium was at least fifteen-fold less effective. The gating of all three channels was independent of the voltage across the bilayer, but was affected by the dihydropyridine calcium channel agonist Bay K 8644 (Bay K). In the presence of Bay K but not in its absence, long discrete gating events were routinely observed, suggesting that the dihydropyridine increased the probability of long open states as it does for calcium channels in other systems. Bilayers invariably contained more than a single channel (or conductance state). This was observed even when the Aplysia nervous system membranes were prepared in the presence of cytoskeleton disrupting agents, or when the membrane proteins were diluted extensively with exogenous phospholipid. Furthermore, transitions between conductance levels were observed with high frequency. These findings, together with the fact that all of the conductance states share certain properties including voltage-independence and sensitivity to Bay K, suggest that the apparent multiple channel types may in fact represent subconductance states of a single ion channel.
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PMID:Calcium and barium permeable channels from Aplysia nervous system reconstituted in lipid bilayers. 244 94

In voltage-gated cation channels, it is thought that residues responsible for ion-selectivity are located within the pore-lining SS1-SS2 segments. In this study, we compared the ion permeation properties of mutant calcium channels in which highly conserved glutamate residues, located at analogous positions in the SS2 regions of all four motifs, were individually replaced. All of the mutants exhibited a loss of selectivity for divalent over monovalent cations. However, the permeation properties of the individual mutants varied in a position dependent manner. The results provide strong evidence that these glutamate residues, positioned at equivalent locations in the aligned sequences, play significantly different roles in forming the selectivity barrier of the calcium channel, and are probably arranged in an asymmetrical manner inside the ion-conducting pore.
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PMID:Differential contribution by conserved glutamate residues to an ion-selectivity site in the L-type Ca2+ channel pore. 790 17

Effect of calcium channel blocker nifedipine on the electrical activity of the brain in anaesthetized rats was studied. The electoencephalographic signals were registered on a computer as series of data and thereafter they were decomposed by Fourier analysis in very narrow fields of frequency. The electrical activity of the brain of the control rats was asymmetrical, with a more important activity in the left brain hemisphere, particularly between 20-30 Hz when the electrical activity of the brain was globally more important. The nifedipine increased the electrical activity of the brain between 0.5-4 Hz and 20-30 Hz in a dose-dependent manner. The drug also increased the interhemispheric asymmetry. Some possible explanations of these effects are analyzed.
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PMID:Effect of nifedipine on electrical activity of the brain in rat. 965 15

Nonproteinaceous calcium channel complexes from Escherichia coli, composed of poly-(R)-3-hydroxybutyrate (PHB) and inorganic polyphosphate (polyP), exhibit two distinct gating modes (modes 1 and 2) in planar lipid bilayers. Here we report the kinetic characterization of the channel in mode 2, a mode characterized by two well-defined conductance levels, a fully open state (87 +/- 3 pS), and a major subconductance state (56 +/- 2 pS). Other subconductance states and full closures are rare (<0.5% of total time). Several kinetic properties of the channel showed asymmetric voltage-dependence indicating an asymmetry in the channel structure. Accordingly, single channels responded to potential change in one of two mirror-image patterns, postulated to arise from opposite orientations of the asymmetrical channel complex in the bilayer. The fraction of time spent in each conductance level was strongly voltage-sensitive. For channels reported in this study, presumably all oriented in the same direction, residence time in the fully open state increased as clamping potentials became more positive whereas residence time in the major subconductance state increased at more negative potentials. Analysis of open time distributions revealed existence of two kinetically distinct states for each level. The shorter time constants for both conductance states exhibited weak voltage-sensitivity; however, the longer time constants were strongly voltage-sensitive. A kinetic scheme, consistent with the complex voltage dependence of the channel, is proposed.
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PMID:Gating kinetics of E. coli poly-3-hydroxybutyrate/polyphosphate channels in planar bilayer membranes. 1043 Jun 57

The localization of cytoplasmic free calcium and a dihydropyridine (DHP) receptor, a putative calcium channel, was recorded during the opposite graviresponses of tip-growing Chara rhizoids and Chara protonemata by using the calcium indicator Calcium Crimson and a fluorescently labeled dihydropyridine (FL-DHP). In upward (negatively gravitropically) growing protonemata and downward (positively gravitropically) growing rhizoids, a steep Ca2+ gradient and DHP receptors were found to be symmetrically localized in the tip. However, the localization of the Ca2+ gradient and DHP receptors differed considerably during the gravitropic responses upon horizontal positioning of the two cell types. During the graviresponse of rhizoids, a continuous bowing downward by differential flank growth, the Ca2+ gradient and DHP receptors remained symmetrically localized in the tip at the centre of growth. However, after tilting protonemata into a horizontal position, there was a drastic displacement of the Ca2+ gradient and FL-DHP to the upper flank of the apical dome. This displacement occurred after the apical intrusion and sedimentation of the statoliths but clearly before the change in the growth direction became evident. In protonemata, the reorientation of the growth direction started with the appearance of a bulge on that site of the upper flank which was predicted by the asymmetrically displaced Ca2+ gradient. With the upward shift of the cell tip, which is suggested to result from a statolith-induced displacement of the growth centre, the Ca2+ gradient and DHP receptors became symmetrically relocalized in the apical dome. No major asymmetrical rearrangement was observed during the following phase of gravitropic curvature which is characterized by slower rates of bending. Labeling with FL-DHP was completely inhibited by a non-fluorescently labeled dihydropyridine. From these results it is suggested that FL-DHP labels calcium channels in rhizoids and protonemata. In rhizoids, positive gravitropic curvature is caused by differential growth limited to the opposite subapical flanks of the apical dome, a process which does not involve displacement of the growth centre, the calcium gradient or calcium channels. In protonemata, however, it is proposed that a statolith-induced asymmetrical relocalization of calcium channels and the Ca2+ gradient precedes, and might mediate, the rearrangement of the centre of growth, most likely by the displacement of the Spitzenkorper, to the upper flank, which results in the negative gravitropic reorientation of the growth direction.
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PMID:Relocalization of the calcium gradient and a dihydropyridine receptor is involved in upward bending by bulging of Chara protonemata, but not in downward bending by bowing of Chara rhizoids. 1055 Jun 22

Dihydropyridine having substituted imidazole at 4-position in conjunction with various C3, C5 diesters have calcium channel antagonist activity. In this paper a group of dialkyl, dicycloalkyl and diaryl ester analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 replaced by 2-methyl-4(5)-chloro-5(4)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle (GPILSM). The results for the symmetrical ester series showed that increasing the length chain in C3 and C5 ester substituents increased activity. When increasing of the length or lipophilicity accompany with increasing the hindrance, the activity decreased. In asymmetrical diester series, the results showed when R1 is methyl or ethyl, increasing of the lipophilic property in R substituent increases the activity if this high lipophilicity don't accompany with steric hindrance. Our results demonstrate that in symmetrical and asymmetrical series aromatic compounds were more active than aliphatic compounds. In symmetrical diesters compounds, the most active compound was diphenylethyl ester derivative, that it was more active than the reference drug nifedipine. These structure activity data indicate that the 2-methyl-4(5)chloro-5(4)-imidazolyl moiety is bioisoester of 2-nitrophenyl and 2-chlorophenyl moieties.
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PMID:Synthesis and calcium channel antagonist activity of nifedipine analogues containing 4(5)-chloro-2-methyl-5(4)-imidazolyl substituent. 1182 26

Various diester analogues of nifedipine, in which the orthonitrophenyl group at position 4 is replaced by 1-methyl-2-methylthio-5-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists on guinea-pig ileal smooth muscle. Nifedipine was used as standard. Comparison of the activities of symmetrical esters (3a-e) indicate that increasing the length of alkyl chain in C3 and C5 ester substituents increases the antagonist activity and the n-propyl ester being preferred (IC50= 2.66 x 10(-9) M). In asymmetrical series (6a-g), compound 6g having ethyl and n-butyl ester at C3 and C5 positions of basic dihydropyridine structure was found to be the most active (IC50= 1.32 x 10(-9) M).
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PMID:Synthesis and calcium channel antagonist activity of nifedipine analogues with methylthioimidazole substituent. 1198 97

A group of alkyl, cycloalkyl and aryl ester analogs of nifedipine, in which the o-nitrophenyl group at position 4 is replaced by a 2-phenyl-4(5)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonist using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle, and the activity of 5a-d, 8b and 8f against pentylenetetrazole (PTZ)-induced seizure was assessed. The results for symmetrical esters showed that lengthening of the methylene chain in C3 and C5 ester substituents increased activity. When increasing of the length is accompanied by increasing the hindrance, the activity decreased. In contrast to symmetrical derivatives, comparison of the activities of asymmetrical esters showed that increasing the length of the methylene chain was accompanied by a decrease in their activity. The results demonstrate that 8a was more active, and 5c and 8f were similar in effect to that of the reference drug nifedipine. The time-course of anticonvulsant effect on PTZ-induced seizure threshold of said compounds was assessed and showed that increasing the lipophilicity decreases the time needed for maximum effect. Mice treated with intraperitoneal injection of 25 mg/kg of these derivatives all exhibited increase seizure threshold as compared with control.
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PMID:Lipophilic 4-imidazoly-1,4-dihydropyridines: synthesis, calcium channel antagonist activity and protection against pentylenetetrazole-induced seizure. 1508 43

A group of cycloalkyl and aryl ester analogues of nifedipine (CAS 21829-25-4), in which the ortho-nitrophenyl group at position 4 is replaced by a 2-phenyl-4(5)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonist using the high K+ contraction of guinea-pig ileal smooth muscle. The results for the symmetrical esters in cycloalkyl and aryl esters showed that increasing the length of the methylene chain in C3 and C5 ester substituents (from n = 0 to n = 3) increased activity. A comparison of the effect of cyclohexyl relative to phenyl substituent showed that cyclohexyl derivatives were more active than phenyl derivatives. In contrast to symmetrical derivatives, comparison of the activities of asymmetrical esters showed that phenyl derivatives were more active than cycloalkyl derivatives. The results demonstrate that compounds 5a, 8a, 8l and 8n had similar activity to and compounds 5b, 5c, 5d and 5i were more active than the reference drug nifedipine. The structure-activity data indicate that the 4-(2-phenyl-4(5)-imidazolyl) moiety is a bioisoester of the o-nitro group of nifedipine.
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PMID:Synthesis and calcium channel antagonist activity of new 1,4-dihydropyridine derivatives containing lipophilic 4-imidazolyl substituents. 1550 Jan 95


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