Shine and rise! GABAA–receptors are ligand-gated chloride channels that respond to the major inhibitory neurotransmitter of the mammalian central nervous system. Herein, we introduce azobenzene derivatives of propofol that increase GABA-induced currents when irradiated with light and thus function as photochromic potentiators. One of our molecules, AP2, can be employed as a light-dependent general anesthetic in translucent tadpoles.

Shine and rise! GABA A -receptors are ligand-gated chloride channels that respond to the major inhibitory neurotransmitter of the mammalian central nervous system. Herein, we introduce azobenzene derivatives of propofol that increase GABA-induced currents when irradiated with light and thus function as photochromic potentiators. One of our molecules, AP2, can be employed as a light-dependent general anesthetic in translucent tadpoles. Keywordspropofol; azobenzenes; GABA receptors; photopharmacology GABA A receptors are pentameric ligand-gated ion channels that are activated by the major inhibitory neurotransmitter in the mammalian brain, γ-aminobutyric acid (GABA). [1] Binding of GABA results in the opening of a chloride ion-selective pore, thusCorrespondence to: Erwin Sigel, erwin.sigel@mci.unibe.ch; Dirk Trauner, dirk.trauner@lmu.de. 1 These authors contributed equally to this work.Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. hyperpolarizing the postsynaptic neuron and decreasing the likelihood of action potential firing. As such, GABA A receptors are a prominent target for anesthetic, hypnotic, and anticonvulsant drugs (Fig. 1). [2,3] While agonists, antagonists and blockers of GABA A receptors, such as muscimol, gabazine, or picrotoxinin, respectively, have proven to be valuable research tools, their impact on human medicine has been limited. Drugs that target these receptors are dominated by allosteric modulators that potentiate, i.e. increase, chloride currents elicited by the neurotransmitter. Well-established potentiators include benzodiazepines (e.g. diazepam), barbiturates (e.g. phenobarbital), the imidazopyridine zolpidem and the simple phenol propofol. [2] These bind to distinct allosteric sites on GABA A receptors increasing the mean open time or the opening frequency of the channel. However, the analysis of their exact binding sites at a molecular level has been complicated by a lack of detailed structural data. NIH Public AccessFollowing its discovery in 1980, propofol has become the most widely used intravenous general anaesthetic. [4] Although its mode of action has not been fully elucidated, it is commonly accepted that the anaesthesia induced by this unusually lipophilic drug mostly results from potentitation of GABA-induced currents, as well as a direct activation of the chloride channel at low concentrations. Propofol has a rapid onset and offset of action and shows only minimal accumulation upon prolonged use. The intravenous administration of propofol is also associated with reduced postoperative nausea and vomiting. [5] While GABA A -receptors respond to a variety of ligands, they are normally not sensitive toward light. It would be fascinating to confer light-sensitivity to these ion channels, since light is unsurpassed in terms of the temporal and spatial precision it provides. This could be indirectly achieved via ligands that act on the receptors but can be optically switched between an active and an inacti...

TRPM channels have emerged as key mediators of diverse physiological functions. However, the ionic permeability relevant to physiological function in vivo remains unclear for most members. We report that the single Drosophila TRPM gene (dTRPM) generates a conductance permeable to divalent cations, especially Zn(2+) and in vivo a loss-of-function mutation in dTRPM disrupts intracellular Zn(2+) homeostasis. TRPM deficiency leads to profound reduction in larval growth resulting from a decrease in cell size and associated defects in mitochondrial structure and function. These phenotypes are cell-autonomous and can be recapitulated in wild-type animals by Zn(2+) depletion. Both the cell size and mitochondrial defect can be rescued by extracellular Zn(2+) supplementation. Thus our results implicate TRPM channels in the regulation of cellular Zn(2+) in vivo. We propose that regulation of Zn(2+) homeostasis through dTRPM channels is required to support molecular processes that mediate class I PI3K-regulated cell growth.

γ-Aminobutyric acid type A receptors (GABAA receptors) are chloride ion channels composed of five subunits, mediating fast synaptic and tonic inhibition in the mammalian brain. These receptors show near five-fold symmetry that is most pronounced in the second trans-membrane domain M2 lining the Cl− ion channel. To take advantage of this inherent symmetry, we screened a variety of aromatic anions with matched symmetry and found an inhibitor, pentacyanocyclopentdienyl anion (PCCP−) that exhibited all characteristics of an open channel blocker. Inhibition was strongly dependent on the membrane potential. Through mutagenesis and covalent modification, we identified the region α1V256-α1T261 in the rat recombinant GABAA receptor to be important for PCCP− action. Introduction of positive charges into M2 increased the affinity for PCCP− while PCCP− prevented the access of a positively charged molecule into M2. Interestingly, other anion selective cys-loop receptors were also inhibited by PCCP−, among them the Drosophila RDL GABAA receptor carrying an insecticide resistance mutation, suggesting that PCCP− could serve as an insecticide.

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