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At least 19 recordsLinked to original sources
PubMed1991

Diffusion model in ion channel gating. Extension to agonist-activated ion channels.

Previously, we described a model which treats ion channel gating as a discrete diffusion problem. In the case of agonist-activated channels at high agonist concentration, the model predicts that the closed lifetime probability density function from single channel recording approximates a power law with an exponent of -3/2 (Millhauser, G. L., E. E. Salpeter, and R. E. Oswald. 1988a. Proc. Natl. Acad. Sci. USA. 85: 1503-1507). This prediction is consistent with distributions derived from a number of ligand-gated channels at high agonist concentration (Millhauser, G. L., E. E. Salpeter, and R. E. Oswald. 1988b. Biophys. J. 54: 1165-1168.) but does not describe the behavior of ion channels at low activator concentrations. We examine here an extension of this model to include an agonist binding step. This extended model is consistent with the closed time distributions generated from the BC3H-1 nicotinic acetylcholine receptor for agonist concentrations varying over three orders of magnitude.

Animals↗
PubMed1991

Four cases of direct ion channel gating by cyclic nucleotides.

Four different nucleotide-gated ion channels are discussed in terms of their biophysical properties and their importance in cell physiology. Channels activated directly by cGMP are present in vertebrate and invertebrate photoreceptors. In both cases cGMP increases the fraction of time the channel remains in the open state. At least three cGMP molecules are involved in channel opening in vertebrate photoreceptors and the concentration of the cyclic nucleotide to obtain the half maximal effect is about 15 microM. The light-dependent channel of both vertebrates and invertebrates is poorly cation selective. The vertebrate channel allows divalent cations to pass through 10-15-fold more easily than monovalent ions. In agreement with their preference for divalent cations, this channel is blocked by l-cis Dialtazem, a molecule that blocks certain types of calcium channels. In olfactory neurons a channel activated by both cAMP and cGMP is found and, as in the light-dependent channel, several molecules of the nucleotide are needed to open the channel with a half maximal effect obtained in the range of 1-40 microM. The channel is poorly cationic selective. A K+ channel directly and specifically activated by cAMP is found in Drosophila larval muscle. At least three cAMP molecules are involved in the opening reaction. Half-maximal effect is obtained at about 50 microM. This channel is blocked by micromolar amount of tetraethylammonium applied internally. Interestingly, this channel has a probability of opening 10-20-fold larger in the mutant dunce, a mutant that possesses abnormally elevated intracellular cAMP level, than in the wild type.

Animals↗
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↗
PubMed1991

Chiral aspects of drug action at ion channels: a commentary on the stereoselectivity of drug actions at voltage-gated ion channels with particular reference to verapamil actions at the Ca2+ channel.

Ion channels may be considered as pharmacological receptors possessing specific drug binding sites with defined structure-activity relationships. Accordingly drug binding to ion channels is stereoselective. Interpretation of this stereoselectivity may be complex because of the existence of differences in affinity and access to different channel states. Such state-dependent interactions may give rise to quantitative and qualitative differences in stereoselectivity. The implications of such differences are reviewed for drug action at Na+, K+ and Ca2+ channels. Detailed attention is paid to the actions of verapamil enantiomers in the cardiovascular system where activities differ in vascular and cardiac tissues because of state-dependent interactions and stereoselective first-oass metabolism.

Animals↗
PubMed1990

Brain alpha-bungarotoxin binding protein cDNAs and MAbs reveal subtypes of this branch of the ligand-gated ion channel gene superfamily.

alpha-Bungarotoxin (alpha Bgt) is a potent, high-affinity antagonist for nicotinic acetylcholine receptors (AChRs) from muscle, but not for AChRs from neurons. Both muscle and neuronal AChRs are thought to be formed from multiple homologous subunits aligned around a central cation channel whose opening is regulated by ACh binding. In contrast, the exact structure and function of high-affinity alpha Bgt binding proteins (alpha BgtBPs) found in avian and mammalian neurons remain unknown. Here we show that cDNA clones encoding alpha BgtBP alpha 1 and alpha 2 subunits define alpha BgtBPs as members of a gene family within the ligand-gated ion channel gene superfamily, but distinct from the gene families of AChRs from muscles and nerves. Subunit-specific monoclonal antibodies raised against bacterially expressed alpha BgtBP alpha 1 and alpha 2 subunit fragments reveal the existence of at least two different alpha BgtBP subtypes in embryonic day 18 chicken brains. More than 75% of all alpha BgtBPs have the alpha 1 subunit, but no alpha 2 subunit, and a minor alpha BgtBP subtype (approximately 15%) has both the alpha 1 and alpha 2 subunits.

Amino Acid Sequence↗
PubMed1992

GABA- and glutamate-gated ion channels as molecular sites of alcohol and anesthetic action.

The evidence presented above indicates that GABA- and glutamate-activated ion channels are molecular sites of alcohol and anesthetic action. In view of the important role that these channels play in CNS excitability, it seems likely that the actions of alcohol and anesthetics on these channels contribute significantly to the behavioral effects of these agents. Although the behavioral effects of alcohol and anesthetics may well result from a combination of actions on different ion channels and other molecular sites in the CNS, it is of interest to consider whether the actions of these agents on particular types of ion channels may contribute to particular behavioral effects. In this regard, it should be noted that benzodiazepines potentiate GABAA responses, but do not produce intoxication or general anesthesia in their clinical dose range. Benzodiazepines are widely used clinically, primarily for their anxiolytic actions (26), suggesting that the potentiation of GABAA responses by ethanol and barbiturates may contribute to the anxiolytic effects of these agents. Since kainate and quisqualate channels mediate fast excitatory transmission in the CNS, inhibition of kainate and quisqualate receptor-activated responses would be expected to result in general CNS depression. This suggests that inhibition of kainate and quisqualate receptor-mediated responses may contribute to the general anesthetic effects of ethanol, trichloroethanol and barbiturates. NMDA channels are thought to mediate complex excitatory neural phenomena and cognitive function. In view of this, the observation that ethanol inhibits NMDA receptor-mediated responses over the concentration range that produces intoxication and the correlation between the potency of different alcohols for inhibiting NMDA-activated current and their potency for producing intoxication suggest that ethanol-induced inhibition of NMDA receptor-mediated responses may contribute to the intoxicating effects of ethanol. Although these speculations are no doubt oversimplifications, the recognition that GABA- and glutamate-gated ion channels are molecular sites of alcohol and anesthetic action provides a basis for investigating the molecular mechanisms involved in the action of these agents and the behavioral significance of those actions.

Alcohols↗
PubMed1990

The neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) can activate a ligand-gated ion channel in Helix neurones.

This report presents evidence that the molluscan neuropeptide FMRFamide can directly activate a ligand-gated ion channel in Helix neurones. Using the patch-clamp technique we have observed unitary currents activated by the application of FMRFamide onto outside-out patches. As for the whole-cell response, Na+ ions are the main charge carriers. We conclude that FMRFamide may act as a fast depolarizing neurotransmitter in the Helix nervous system.

Animals↗
PubMed1992

Receptor classes and the transmitter-gated ion channels.

Transmitter-gated channels, which can be selective for cations or for anions, form an important class among the membrane receptors responsible for signal transduction. Thirteen principal types of these channels can now be recognized and most of these are available for analysis in recombinant form. It is instructive to contrast their characteristic structural features with those of the two other primary classes of the signal-transducing receptors of membranes.

Animals↗
PubMed1987

Mitogens and oncogenes can block the induction of specific voltage-gated ion channels.

The mechanisms underlying the ontogeny of voltage-gated ion channels in muscle are unknown. Whether expression of voltage-gated channels is dependent on mitogen withdrawal and growth arrest, as is generally true for the induction of muscle-specific gene products, was investigated in the BC3H1 muscle cell line by patch-clamp techniques. Differentiated BC3H1 myocytes expressed functional Ca2+ and Na+ channels that correspond to those found in T tubules of skeletal muscle. However, Ca2+ and Na+ channels were first detected after about 5 days of mitogen withdrawal. In order to test whether cellular oncogenes, as surrogates for exogenous growth factors, could prevent the expression of ion channels whose induction was contingent on mitogen withdrawal, BC3H1 cells were modified by stable transfection with oncogene expression vectors. Expression vectors containing v-erbB, or c-myc under the control of the SV40 promoter, delayed but did not prevent the appearance of functional Ca2+ and Na+ channels. In contrast, transfection with a Val12 c-H-ras vector, or cotransfection of c-myc together with v-erbB, suppressed the formation of functional Ca2+ and Na+ channels for greater than or equal to 4 weeks. Potassium channels were affected neither by mitogenic medium nor by transfected oncogenes. Thus, the selective effects of certain oncogenes on ion channel induction corresponded to the suppressive effects of mitogenic medium.

Calcium↗
PubMed1991

Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study.

Recent studies from our laboratory have provided evidence that the 1-amino-adamantane derivative memantine (1-amino-3,5-dimethyl-adamantane) binds to the MK-801-binding site of the N-methyl-D-aspartate (NMDA)-receptor-gated ion channel. This action has been suggested to account for the antiparkinsonian and antispastic activity of the drug. In the present investigation we have extended our work by testing a series of 1-amino-adamantanes, including amantadine (1-amino-adamantane) and memantine, for their ability to compete with [3H]MK-801 binding in membrane homogenates of postmortem human frontal cortex. The most potent substance (1-amino-3,5-diethyl-adamantane) had a Ki-value of 0.19 +/- 0.06 microM while the weakest substance (1-N-methyl-amino-adamantane) had a Ki-value of 21.72 +/- 1.63 microM. The Ki-value of amantadine was 10.50 +/- 6.10 microM. In agreement with our earlier investigation, the Ki-value of memantine was 0.54 +/- 0.23 microM. The results indicate that 1-amino-adamantanes, in general, may produce their pharmacological effects through an interaction with the NMDA-receptor-gated ion channel. The displacement of [3H]MK-801 binding thus may provide the basis to predict the antiparkinsonian and antispastic activity of novel substituted 1-amino-adamantanes and possibly of other drugs.

Adamantane↗
PubMed1992

Phosphorylation of ligand-gated ion channels: a possible mode of synaptic plasticity.

Most neurotransmitter receptors examined to date have been shown either to be regulated by protein phosphorylation or to contain consensus sequences for phosphorylation by protein kinases. Neurotransmitter receptors that mediate rapid synaptic transmission in the nervous system are the ligand-gated ion channels and include the nicotinic acetylcholine receptors of muscle and nerve and the excitatory and inhibitory amino acid receptors: the glutamate, GABAA, and glycine receptors. These receptors are multimeric proteins composed of homologous subunits which each span the membrane several times and contain a large intracellular loop that is a mosaic of consensus sites for protein phosphorylation. Recent evidence has suggested that extracellular signals released from the presynaptic neuron, such as neurotransmitters and neuropeptides as well as an extracellular matrix protein, regulate the phosphorylation of ligand-gated ion channels. The functional effects of phosphorylation are varied and include the regulation of receptor desensitization rate, subunit assembly, and receptor aggregation at the synapse. These results suggest that phosphorylation of neurotransmitter receptors represents a major mechanism in the regulation of their function and may play an important role in synaptic plasticity.

Amino Acid Sequence↗
PubMed1992

Molecular model of the cyclic GMP-binding domain of the cyclic GMP-gated ion channel.

The structure of the cyclic GMP-binding domain of the cyclic GMP-gated ion channel from bovine retinal rod photoreceptors has been modeled by analogy to the crystal structure of the homologous cyclic AMP-binding domain of catabolite gene activator protein (CAP). The modeled cyclic GMP-binding domain has a three-residue deletion and a five-residue insertion between beta strands compared to CAP. The major interactions of the ion channel with cyclic GMP are similar to those observed for cyclic AMP bound to CAP and predicted for cGMP bound to the cGMP-dependent protein kinase: Gly 543 and Glu 544 make hydrogen-bond interactions with the ribose 2'-OH, Arg 559 forms an ion pair with the charged phosphate oxygen, and Thr 560 forms hydrogen-bond interactions with an exocyclic phosphate oxygen and with the 2-amino group of cGMP. Three additional potential interactions were predicted from the model structure. Ile 545 O and Ser 546 OH form hydrogen-bond interactions with an exocyclic phosphate oxygen, and Phe 533 may interact with the aromatic ring of cGMP. This model is in agreement with both the analogue binding experiments and the mutational analysis of Thr 560.

Amino Acid Sequence↗