The C. elegans heterochronic gene pathway consists of a cascade of regulatory genes that are temporally controlled to specify the timing of developmental events1. Mutations in heterochronic genes cause temporal transformations in cell fates in which stage-specific events are omitted or reiterated2. Here we show that let-7 is a heterochronic switch gene. Loss of let-7 gene activity causes reiteration of larval cell fates during the adult stage, whereas increased let-7 gene dosage causes precocious expression of adult fates during larval stages. let-7 encodes a temporally regulated 21-nucleotide RNA that is complementary to elements in the 3′ untranslated regions of the heterochronic genes lin-14, lin-28, lin-41, lin-42 and daf-12, indicating that expression of these genes may be directly controlled by let-7. A reporter gene bearing the lin-41 3′ untranslated region is temporally regulated in a let-7-dependent manner. A second regulatory RNA, lin-4, negatively regulates lin-14 and lin-28 through RNA–RNA interactions with their 3′ untranslated regions3,4. We propose that the sequential stage-specific expression of the lin-4 and let-7 regulatory RNAs triggers transitions in the complement of heterochronic regulatory proteins to coordinate developmental timing.

The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans

The Cationminus signpi Interaction.

Pentameric ligand gated ion-channels, or Cys-loop receptors, mediate rapid chemical transmission of signals. This superfamily of allosteric transmembrane proteins includes the nicotinic acetylcholine (nAChR), serotonin 5-HT3, gamma-aminobutyric-acid (GABAA and GABAC) and glycine receptors. Biochemical and electrophysiological information on the prototypic nAChRs is abundant but structural data at atomic resolution have been missing. Here we present the crystal structure of molluscan acetylcholine-binding protein (AChBP), a structural and functional homologue of the amino-terminal ligand-binding domain of an nAChR alpha-subunit. In the AChBP homopentamer, the protomers have an immunoglobulin-like topology. Ligand-binding sites are located at each of five subunit interfaces and contain residues contributed by biochemically determined 'loops' A to F. The subunit interfaces are highly variable within the ion-channel family, whereas the conserved residues stabilize the protomer fold. This AChBP structure is relevant for the development of drugs against, for example, Alzheimer's disease and nicotine addiction.

Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.

https://www2.mrc-lmb.cam.ac.uk/groups/nu/pdf/jmb05.pdf

Refined Structure of the Nicotinic Acetylcholine Receptor at 4A Resolution

▪ Abstract The neonicotinoids, the newest major class of insecticides, have outstanding potency and systemic action for crop protection against piercing-sucking pests, and they are highly effective for flea control on cats and dogs. Their common names are acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. They generally have low toxicity to mammals (acute and chronic), birds, and fish. Biotransformations involve some activation reactions but largely detoxification mechanisms. In contrast to nicotine, epibatidine, and other ammonium or iminium nicotinoids, which are mostly protonated at physiological pH, the neonicotinoids are not protonated and have an electronegative nitro or cyano pharmacophore. Agonist recognition by the nicotinic receptor involves cation-π interaction for nicotinoids in mammals and possibly a cationic subsite for interaction with the nitro or cyano substituent of neonicotinoids in insects. The low affinity of neonicotinoids for vertebrate ...

NEONICOTINOID INSECTICIDE TOXICOLOGY: Mechanisms of Selective Action

The effects of niflumic acid and flufenamic acid, two nonsteroidal anti-inflammatory agents known to block anion transport in red blood cells, on Ca2(+)-activated Cl- currents (ICl(Ca)) in Xenopus oocytes were examined. Both compounds reversibly inhibited ICl(Ca), elicited in response to depolarizing voltage steps, in a dose-dependent manner, with no effect on the shape of the current-voltage curve. The apparent inhibition constant for niflumic acid was 17 microM, whereas that for flufenamic acid was 28 microM. Niflumic acid also inhibited ICl(Ca) elicited by bath application of Ca2+ to oocytes permeabilized using the Ca2+ ionophore A23187, demonstrating that the inhibition of ICl(Ca) is due to a direct interaction with the Cl- channel, rather than by interference with Ca2+ entry through voltage-dependent Ca2+ channels. In addition to their use in the elimination of ICl(Ca) as a possible source of artifact when Xenopus oocytes are used as an expression system for exogenous ion channels and receptors, it is expected that these two compounds will find use as potent anion channel blockers.

Niflumic and flufenamic acids are potent reversible blockers of Ca2(+)-activated Cl- channels in Xenopus oocytes.

A voltage-gated anion channel from the electric organ of Torpedo californica.

A highly conserved leucine is found in the middle of the porelining (M2) domain of the members of the ligand-gated ion channel family. Two very different roles have been proposed for this leucine. In one model, this residue swings into the lumen of the channel during desensitization to form the nonconducting desensitized state, whereas in the other model, the leucines from each subunit interact with each other to form a constriction in the channel that constitutes the actual gate of the channel. We examined the role of this leucine in the muscle-type acetylcholine receptor by replacing it with the polar amino acid threonine. Replacement of the leucine in any one subunit slows desensitization and shifts the dose-response relationship toward lower concentrations. Replacement of leucines in additional subunits leads to progressively larger shifts in the dose-response curves. The shift depends only on the number of leucines replaced, not on which particular subunits contain the mutation; in other words, the mutations act independently. At the single-channel level, the mutation greatly increases the channel mean open time. We conclude that the role of the conserved leucine is to set the mean open time of the channel through interactions with other regions of the receptor rather than to serve as the gate per se of the ion channel.

The role of conserved leucines in the M2 domain of the acetylcholine receptor in channel gating.

https://www.cell.com/neuron/pdf/0896-6273(88)90156-0.pdf

Charybdotoxin block of Shaker K+ channels suggests that different types of K+ channels share common structural features

During the past few years, we have been studying the possibility of incorporating ion-conductance channels from animal cell membranes into artificial bilayers, as a first step towards characterizing these channels in a biochemically defined system. The strategy for this work is to bring about the fusion of native membrane vesicles with a planar phospholipid bilayer, a system upon which electrical conductance may be measured at a controllable applied voltage. Using this approach, we have documented the existence of a voltage-gated K+-selective channel from rabbit sarcoplasmic reticulum (SR) .1-4 In attempting to extend the technique to other and better-understood membrane systems, we recently showed that “microsac” vesicles of the electric organ of Torpedo californica, an electric ray whose electroplax membrane carries a high concentration of acetylcholine receptor, can be made to induce a large increase in conductance of planar b i l aye r~ .~ Quite surprisingly, this microsac-induced conductance had no properties to be expected of the acetylcholine-gated channel, but rather displayed anion selectivity and voltage-dependence, along with clear single-channel fluctuation behavior. In this paper, we extend the initial results presented on this channel. The major new finding here is that the channel is exquisitely selective to chloride ion and is actually blocked by certain other anions. In addition, we demonstrate the asymmetric inhibition of the channel by those anion-transport workhorses, SITS and DIDS. While we can only speculate upon the physiological role of the system, we consider that the results demonstrate that the C1channel is present in the electroplax of Torpedo and that it must be taken into account in any model of the operation of this cell.

A voltage-dependent chloride conductance channel from torpedo electroplax membrane*

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