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PubMed2002

The effects of general anaesthetics on ligand-gated ion channels.

The experimental effort that has been expended in investigating the effects of general anaesthetics on LGICs has been enormous over the past decade. Members of all three LGIC superfamilies have been examined using electrophysiological techniques. Anaesthetics that have been examined include volatile anaesthetics, gaseous anaesthetics, alcohols, i.v. anaesthetics and non-immobilizers. Obsolete anaesthetics (ether, cyclopropane, butane) have been used in order to increase the variability of the structure and polarity of experimental compounds. The tools of molecular biology have been used to make chimeric receptors and to make single-site mutations. Interestingly, this work has been taking place in parallel with efforts to understand the structure of these proteins. Anaesthetic research often stimulates structural research as well as vice versa. There are some common themes in the interactions between anaesthetics and the three superfamilies of LGICs. In many cases, anaesthetics have both inhibitory and potentiating effects on the channels. It is likely that the number of examples of this will increase when experiments are designed to look specifically for one or the other type of effect. So we must conclude that there are multiple binding sites for anaesthetics on LGICs. The degree of inhibition or potentiation is not easily predictable. In retrospect, this is not surprising when we consider that the sensitivity of a channel to anaesthetics can be altered by a single amino-acid mutation. The large structural differences between the cys-loop, glutamate-activated and P2X superfamilies do not lead to large differences in anaesthetic sensitivity. It is the smaller, almost insignificant, changes that do this. This observation that small changes may lead to large effects reinforces the idea that at least some of the interactions between anaesthetics and LGICs are direct drug-protein interactions that are not mediated by the lipids. This review has not addressed the question of whether the effects of anaesthetics seen on LGICs are relevant to anaesthesia. This question cannot really be answered at present. Although potent effects can be observed on the channels themselves, we have only begun to try to understand whether these effects are important for a synapse, a neuronal circuit or the function of an animal's nervous system. We have studied the trees; now we must go on to study the forest and the ecosystem.

Anesthetics, General↗
PubMed2005

Mutational studies using a cation-conducting GABAA receptor reveal the selectivity determinants of the Cys-loop family of ligand-gated ion channels.

The present study evaluates how four key amino acid residue positions (- 4' to - 1') within the M1-M2 linker of the GABA(A) receptor beta subunit influences ion selectivity of a cation-conducting GABA receptor. Cation selectivity was found to be highly dependent on the side-chains of the amino acid residues present. The critical factor for cation selectivity was the presence of a negatively charged Glu or Asp residue in the -1' position. Receptors containing the neutral amino acids Gln or Asn or a positively charged Arg residue were anion selective. In the presence of a -1' Glu residue, the amino acids in adjacent positions were also found to be important determinants of cation selectivity. Moreover, the length of the M1-M2 linker as well as the presence of a Pro residue within this segment also affected ion selectivity, suggesting that the local environment and three-dimensional position of the -1' Glu are essential determinants of cation permeation. Conversely, no specific amino acid residues were found to be essential for anion selectivity, suggesting that the basic architecture of the selectivity segment of this class of receptor channels is optimally suited for anion conduction.

Amino Acid Sequence↗
PubMed1997

Regulation of voltage-gated ion channels during ascidian embryogenesis.

In the proto-chordate Halocynthia roretzi, a voltage-activated sodium current undergoes a change in kinetics within 48 h of fertilization. Molecular cloning and microinjection of antisense DNA into single cells suggest that the kinetic changes are due to the increased expression of a neural-specific sodium channel gene, TuNa I. TuNa I gene transcription is first induced in late-stage gastrulae, preceding the appearance of the rapidly inactivating sodium current unique to alpha 4-2 derived neural cells. In cleavage-arrested and intact embryos, cell interactions between specific animal and vegetal blastomeres are required for induction of TuNa I gene expression. By contrast, another sodium channel gene, TuNa II, is mainly expressed in neural cells of the alpha 4-1 lineage. In this lineage, cells of endoderm, notochord and muscle develop. TuNa II gene transcription occurs in isolated alpha 4-1 blastomeres without interacting with other lineage cells. Thus, there are two distinct neural cell lineages in the ascidian tadpole: one is similar to the ectoderm-derived neural tissue controlled by a mechanism reminiscent of the neural induction in the vertebrate, the other is the lineage of posterior neural tube in which motor neurons develop in close association with the notochord or muscle lineage.

Animals↗
PubMed2005

Suppressive effects of red wine polyphenols on voltage-gated ion channels in dorsal root ganglionic neuronal cells.

Polyphenols are ubiquitous plant metabolites with multiple pharmacological properties. Using whole-cell patch-clamp current recording techniques, we studied the effects of polypnenols extracted from red wine (purity > 90% from Cabernet Sauvignon grape wine) on the activities of voltage-operated Na+-, K+-, and Ca2+-channel currents in mouse dorsal root ganglionic neuronal cells. The polyphenols suppressed all of the channel activities with half-effective concentrations of about 2.5, 4.0, and 0.8-1.5 micro g/ml, respectively. In contrast, they showed no noticeable effects on the ion channels in other types of cells, including large conductance K+-channels in mouse lacrimal acinar cells. Thus, the polyphenols suppress firings of the action potential in the neuronal cells and could show a sedative effect on the excitation. We expect that red wine can be used as a remedy for excessive sensory stimuli.

Animals↗
PubMedDate not supplied

[Effects of opioid analgesics on potential-gated ion channels in the pond snail neurons].

The effects of opioid analgesics morphine, promedol, tramadol, and butorphanol on the transmembrane calcium, sodium, and potassium (fast and slow) ion currents in pond snail (Lymnaea stagnalis) neurons were studied by intracellular dialysis and membrane potential (voltage-clamp) measurements. It was established that all these drugs produce a dose-dependent reversible inhibition of the ion currents (sodium calcium potassium) and reduce nonspecific leak currents, thus producing a stabilizing action upon the sample membrane. The current-inhibiting effect of morphine was not eliminated by naloxone (500 microM); moreover, the latter drug significantly inhibited the ion currents as well.

Analgesics, Opioid↗
PubMed1992

Glutamate-gated ion channels in the brain. Genetic mechanism for generating molecular and functional diversity.

L-glutamate is the major excitatory neurotransmitter in the vertebrate central nervous system. Most cells are responsive to glutamate which activates cation channels with different pharmacological, kinetic, and ion permeability properties. These channels play important roles in neurotransmission, memory acquisition as well as acute and chronic disorders of the brain. The present report summarizes recent knowledge on AMPA (a-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid) receptors which mediate fast synaptic neurotransmission.

Animals↗