Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histrionicotoxin, a spiropiperidine alkaloid, and twenty-two analogs inhibited binding of [3H]perhydrohistrionicotoxin [( 3H]H12-HTX) and of [3H]phencyclidine [( 3H]PCP) to sites on the acetylcholine receptor-ion complex of Torpedo electroplax membranes. Structural alterations to the nitrogen (secondary amine) or oxygen (alcohol) functions or to the five carbon and four carbon side chain of histrionicotoxin altered the potency versus [3H]H12-HTX and [3H]PCP binding measured in the presence or absence of a receptor agonist, carbamylcholine. Histrionicotoxin itself was 3-fold more potent versus [3H]PCP binding than versus [3H]H12-HTX binding. N-Methylation or O-acetylation increased this difference, while alterations to the side chains either slightly decreased or markedly increased this difference. Histrionicotoxin was some 3.5-fold more potent versus [3H]H12-HTX binding in the presence of carbamylcholine than in its absence. O-Acetylation increased this selectivity for the carbamylcholine-activated state of the receptor channel complex, while alterations in the side chains either reduced or increased the selectivity. Histrionicotoxin was some 2.2-fold more potent versus [3H]PCP binding in the presence of carbamylcholine than in its absence. N-Methylation of O-acetyl-histrionicotoxin greatly increased this selectivity, while alterations in the side chains either reduced or had no effect on selectivity.
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PMID:Binding of [3H]perhydrohistrionicotoxin and [3H]phencyclidine to the nicotinic receptor-ion channel complex of Torpedo electroplax. Inhibition by histrionicotoxins and derivatives. 241 60

The present review deals with the molecular mechanisms and elementary phenomena underlying the activation of the voltage- and chemo-sensitive membrane macromolecules: sodium- and potassium-ion channels and nicotinic ACh receptors and their associated ion channel. To achieve an understanding of their various kinetics and conformational states, a number of novel alkaloids, BTX, HTXs, gephyrotoxins, and certain psychotomimetic drugs such as phencyclidine, and many other pharmacologically active agents have been used. Biochemical assays and various electrophysiological techniques have been used in a number of biological preparations--e.g., Torpedo membranes, brain synaptosomes, amphibian and mammalian neuromuscular preparations--to describe the action of such agents. The availability of BTX and scorpion toxins together with aconitine and veratridine as activators and TTX and STX as antagonists of the voltage-sensitive sodium channels, made possible the identification and the physiological and pharmacological characterization of these channels. These studies provided the basis for understanding the mechanisms underlying electrical excitability and culminated, more recently, in the purification and reconstitution of sodium channels from rat brain and in the successful cloning of these channels with the elucidation of their primary structure. We now know that the sodium channel has a molecular mass of 316,000 daltons, consists of five subunits, and has multiple sites for various ligands. In contrast to sodium channels, various classes of potassium channels (inward and outward rectifier potassium channels and Ca(2+)-activated potassium channels) have been described. Unlike the sodium channels, there are no known specific activators for potassium channels. However, a number of potassium channel blockers such as 4-aminopyridine, HTX, histamine, and norepinephrine have been identified which complement the varying types of potassium channels in different neurons. One class of potassium channel blockers with profound medical and social implications comprises PCP and its analogues. The blockade of the potassium-induced 86Rb+ efflux from brain cells, the resulting prolongation of muscle and nerve action potentials, and the increase in transmitter release observed with PCP and some analogues are all highly suggestive of a role for the potassium channel in the behavioral effects of these drugs and its potential involvement in schizophrenia. A number of toxic principles of both plant and animal origin played a significant role in the development of our knowledge about the nAChR.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Macromolecular sites for specific neurotoxins and drugs on chemosensitive synapses and electrical excitation in biological membranes. 248 4

The actions of the tertiary local anesthetic bupivacaine were studied on the nicotinic receptor-ionic channel complex (AChR) using electrophysiological and biochemical methods. Voltage clamp studies of the frog sartorius and cutaneous pectoris neuromuscular junction revealed a concentration-dependent depression of the decay time constant of the end-plate (tau EPC) and spontaneous miniature end-plate (tau MEPC) currents. The relationship of the reciprocal of either tau EPC or tau MEPC and bupivacaine concentration up to 100 microM was linear. Voltage dependence of EPC over the range +60 to -150 mV was reduced, whereas both EPC and MEPC decays were adequately described by a single exponential function at all concentrations tested. Peak MEPC and EPC amplitudes were also depressed in a concentration-dependent manner such that 100 microM bupivacaine reduced peak amplitude by about 50%. The current-voltage relationship remained linear under all conditions tested. Nerve-evoked responses were difficult to study at concentrations greater than 100 microM because of apparent blockade of nerve conduction. Extracellular recording of the MEPC afforded results similar to those obtained with EPCs. The tau MEPC could be reduced to less than 300 mu sec at a bupivacaine concentration of 400 microM. Fluctuation analysis showed that bupivacaine at concentrations of 10 and 25 microM did not change channel conductance but decreased single-channel lifetime to 76% and 39% of control values, respectively. Biochemical studies were performed on Torpedo californica membrane fragments using [3H]phencyclidine ([3H]PCP) and [3H]perhydrohistrionicotoxin ([3H]H12-HTX) as channel probes. Bupivacaine inhibited the binding of [3H]PCP and [3H]H12-HTX with inhibition constants (Ki) of 32 and 25 microM, respectively. The corresponding inhibition constants for bupivacaine methiodide were 1.8 and 3.2 microM. The preincubation of the membranes with carbamylcholine increased the affinity of bupivacaine for the ionic channel sites 5- to 8-fold and the affinity of bupivacaine methiodide 3- to 4-fold. Bupivacaine, however, had no affinity for the agonist recognition site as determined by [3H]ACh and [125I]alpha-bungarotoxin bindings. The electrophysiological and biochemical studies indicate that bupivacaine reacts primarily with the ionic channel of the nicotinic AChR. The results are consistent with a sequential model in which the drug interacts with the sites at the ionic channel of AChR in its open conformation, producing species with little or no conductance. From the present studies there is no evidence for an interaction of bupivacaine with the agonist binding site or closed states of AChR.
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PMID:Interactions of bupivacaine with ionic channels of the nicotinic receptor. Electrophysiological and biochemical studies. 609 Aug 84

We demonstrated previously that a phencyclidine-displaceable quinacrine binding site exists at the lipid-protein interface of the Torpedo acetylcholine receptor (AcChR) (Valenzuela, C. F., Kerr, J. A., and Johnson, D. A. (1992) J. Biol. Chem. 267, 8238-8244). In this manuscript, we assess (1) the transverse position of this site in the lipid bilayer by examining the ability of a series of paramagnetic n-doxyl stearates (n-SALs) and iodide to quench receptor-bound quinacrine and membrane-partitioned octadecyl rhodamine B (C18-Rho) fluorescence and (2) the stoichiometry of histrionicotoxin- or phencyclidine-displaceable quinacrine binding. Initial experiments established what fraction of the n-doxyl stearates partitioned into the membranes and that the n-doxyl stearates do not interfere with quinacrine binding to the receptor at the concentrations used in the quenching studies. The n-doxyl stearate quenching experiments indicated relatively small (< 2) differences between the n-doxyl stearates to quench receptor-bound quinacrine fluorescence, with a rank order of 7-SAL > or = 5-SAL > 12-SAL > 16-SAL. This contrasts with the n-doxyl stearate quenching of the membrane-partitioned C18-Rho which showed as much as an 8.6-fold difference between the various isomers with a rank order of quenching efficiencies of 5-SAL > 7-SAL > 12-SAL > or = 16-SAL. Iodide quenching measurements indicated significant solute accessibility to membrane-partitioned C18-Rho but not to receptor-bound quinacrine. The ratios of the bimolecular quenching rate constants for free to bound quinacrine and for free rhodamine B to membrane-partitioned C18-Rho were 53.4 and 6.6, respectively. Direct titration of quinacrine into suspensions of a high concentration of AcChR-associated membranes yielded an upper limit to the binding stoichiometry of 1.4 HTX- or PCP-displaceable quinacrine binding sites/AcChR functional units. The results suggest that there is a single phencyclidine- or histrionicotoxin-displaceable quinacrine binding site located at or somewhat below the level of the C5-C7 in the phospholipid acyl chains at the lipid-protein interface.
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PMID:Transverse localization of the quinacrine binding site on the Torpedo acetylcholine receptor. 845 5