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Biomedical subjects

K L Swanson

Publications and source records attributed to K L Swanson.

27 records · Page 2Linked to original sources
PubMed1989

Agonist recognition site of the peripheral acetylcholine receptor ion channel complex differentiates the enantiomers of nicotine.

The multiple actions of nicotine enantiomers at the peripheral nicotinic acetylcholine receptor were evaluated using electrophysiological and biochemical techniques. The alpha-bungarotoxin binding site showed a 6-fold greater affinity for (-)-nicotine than for the (+)-isomer, and this stereoselectivity was reflected in differences in the ability of the alkaloids to activate physiological responses in the forms of single ion channel currents, endplate depolarizations and muscle contractures. (-)-Nicotine was also more potent to induce slow desensitization. In contrast, both (-)- and (+)-nicotine were equipotent as ion channel blockers. Ion channel blockade occurred at effective agonist concentrations for (+)-nicotine but above the effective concentration for (-)-nicotine. The rapid and reversible interaction of nicotine enantiomers with the ion channel occurred at concentrations which implicate a significant contribution of channel blockade to the inhibition of indirect muscle twitch. The agonistic and ion channel blocking effects of the nicotine enantiomers provide important clues regarding the mechanisms by which nicotine may affect central nervous system nicotinic receptors.

Animals↗
PubMed1988

Methyllycaconitine and (+)-anatoxin-a differentiate between nicotinic receptors in vertebrate and invertebrate nervous systems.

Specific high-affinity binding sites for 125I-alpha-bungarotoxin and (-)-[3H]nicotine have been measured in rat brain and locust (Schistocerca gregaria) ganglia. The binding sites for 125I-alpha-bungarotoxin had similar Kd values of 1.5 x 10(-9) and 0.8 x 10(-9) M for rat and locust preparations, respectively; the corresponding values for the (-)-[3H]nicotine-binding site were 9.3 x 10(-9) and 1.7 x 10(-7) M. Methyllycaconitine (MLA) potently inhibited 125I-alpha-bungarotoxin binding in both rat and locust. MLA was a less effective inhibitor of (-)-[3H]nicotine binding whereas (+)-anatoxin-a was a very potent inhibitor at this site in the rat but not in the locust. These data suggest that (+)-anatoxin-a is a useful probe for the high-affinity nicotine-binding receptor in vertebrate brain, whereas MLA is a preferential probe for the subclass of receptor that binds alpha-bungarotoxin.

Aconitine↗
PubMed1987

Nicotinic acetylcholine receptors in cultured neurons from the hippocampus and brain stem of the rat characterized by single channel recording.

Single channel recording techniques have been applied to neurons cultured from the hippocampus and the respiratory area of the brain stem of fetal rats in order to search for nicotinic acetylcholine receptors (nAChR) in the central nervous system. In addition to acetylcholine (ACh), the potent and specific agonist (+)-anatoxin-a was also used to characterize nicotinic channels. nAChRs were concentrated on the somal surface near the base of the apical dendrite, and in some patches their density was sufficient to record 2 or more channel openings simultaneously. Although a multiplicity of conductance states was also evident, the predominant population showed a single channel conductance of 20 pS at 10 degrees C. Thus, these neuronal nAChRs resembled the embryonic or denervated-type nAChRs in muscle. However, channel opening and closing kinetics were faster than reported for similar conductance channels in muscle. Therefore the nicotinic channels described here are similar but not identical to those of the well-characterized muscle nAChR, in agreement with biochemical, pharmacological, and molecular genetic studies on brain AChR.

Animals↗
PubMed1987

Interaction of narcotic antagonist naltrexone with nicotinic acetylcholine receptor.

The interactions of naltrexone with the nicotinic acetylcholine receptor were studied electrophysiologically using the frog sciatic nerve-sartorius muscle and biochemically using membranes from the electric organ of Torpedo ocellata. At nanomolar concentrations naltrexone increased the peak amplitude of endplate currents with little change in the decay time constant. At micromolar concentrations there was a concentration-dependent depression of endplate current and miniature endplate current amplitudes and decay time constants. Decay time constant depression was enhanced with hyperpolarization. Only marginal curvature was induced in peak endplate current amplitude versus membrane voltage plots by naltrexone. Naltrexone had no effect on single channel conductance but decreased open channel lifetime, according to fluctuation analysis. Naltrexone alone (less than or equal to 3 microM) did not impair binding of [125I]alpha-bungarotoxin to the receptor in a fast pre-equilibration assay, but increased the ability of acetylcholine to displace [125I]alpha-bungarotoxin. The drug displaced the agonist-stimulated binding of [3H]perhydrohistrionicotoxin to the channel site. Biphasic functional changes in neuromuscular transmission can be attributed to an allosteric mechanism with increased agonist binding to the nicotinic receptor at nanomolar concentrations and caused a non-competitive blockade of the ionic channel at micromolar concentrations.

Amphibian Venoms↗
PubMed1987

Nicotinic acetylcholine receptor ion channel blockade by cocaine: the mechanism of synaptic action.

The action of cocaine on neuromuscular transmission of the frog has been studied to unveil the molecular site upon which this agent acts to block synaptic function. Indirectly elicited twitches of the sciatic nerve-sartorius muscle were reduced at greater than or equal to 50 microM cocaine. The electrically evoked action potentials of muscle membrane were inhibited at 200 microM cocaine, in a manner consistent with a local anesthetic effect. At the synaptic region, the quantal release of transmitter from the nerve terminal was not affected by cocaine at concentrations up to 100 microM. The most potent action of cocaine was the blockade of the ion channel of the nicotinic acetylcholine receptor. Transient membrane depolarization induced by microiontophoresis of acetylcholine was reduced to 7% of control at 50 microM cocaine in a dose-related manner; receptor desensitization was affected to a lesser extent by cocaine at all concentrations tested. The decay time constants of endplate currents were reduced at concentrations greater than or equal to 10 microM. The single channel conductances remained unchanged whereas the channel lifetimes were greatly reduced at 25 and 50 microM of the drug. Unblocking could not be discerned from the observed kinetics of either endplate current decay or single channel closed durations. However, with a combination of 10 microM cocaine and 0.4 M ethanol the endplate currents became biphasic. This suggested a blocking of open ion channels of the nicotinic receptor by cocaine followed by dissociation of acetylcholine from the blocked channel (in the absence of ethanol).

Acetylcholine↗
PubMed1986

Molecular mechanisms of the potent and stereospecific nicotinic receptor agonist (+)-anatoxin-a.

Anatoxin-a (AnTX) was shown to be a highly potent and stereospecific agonist at nicotinic synapses in frog skeletal muscle and Torpedo electric organs. AnTX binds to the nicotinic-acetylcholine receptor with a higher affinity than for acetylcholine (ACh) but does not bind to sites in the receptor-gated ionic channel. (+)AnTX caused receptor desensitization, i.e., the loss of agonist-stimulated binding of histrionicotoxin to an allosteric site with time, at a rate significantly slower than that of ACh. Single channel patch clamp recordings indicated that the conductance of channels activated by (+)AnTX (28 pS) and ACh (27 pS) were similar. The (+)AnTX-activated channels contained rapid closing events, the burst times caused by the toxin were shorter than those caused by ACh but had similar voltage dependencies, and the number of short closures per burst was constant at all potentials with both agonists. The bursts of rapid openings and rapid closures (tau = 0.4 msec) appear to result from repetitive opening and closing of the (+)AnTX-bound receptor-ion channel. It is concluded that the semirigid molecule and secondary amine (+)AnTX is a more potent agonist than ACh or carbamylcholine because of a higher affinity for the receptor. At various concentrations the toxin activates the appearance of channels with the same conductances as ACh-induced channels but with a shorter channel lifetime.

Acetylcholine↗
PubMed1977

Avian muscular dystrophy: functional and biochemical improvement with diphenylhydantoin.

Chicks affected with hereditary muscular dystrophy were injected twice daily with 20 milligrams of diphenylhydantoin per kilogram of body weight on days 1 to 40 after hatching. The righting ability of dystrophic chicks treated with diphenylhydantoin was improved compared to that of untreated dystrophic chicks, and acetylcholinesterase activity was reduced to normal levels in the posterior latissimus dorsi muscles.

Acetylcholinesterase↗