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The interface between extracellular and transmembrane domains of homomeric Cys-loop receptors governs open-channel lifetime and rate of desensitization.

ABSTRACT: The lifetimes of activated postsynaptic receptor channels contribute to the efficiency of synaptic transmission. Here we show that structural differences within the interface dividing extracellular and transmembrane domains of homomeric alpha7 and 5-HT(3A) receptors account for the large differences in open-channel lifetime and time of desensitization onset between these contrasting members of the Cys-loop receptor superfamily. For alpha7 receptors, agonist-evoked single-channel currents appear mainly as isolated brief openings (tau(o) = 0.35 ms), whereas macroscopic currents after a step pulse of agonist desensitize rapidly (tau(d) = 0.4 ms). In contrast for 5-HT(3A) receptors, agonist-evoked single-channel currents appear as clusters of many long openings in quick succession (tau(cluster) = 1.2 s), whereas macroscopic currents desensitize slowly (tau(d) = 1.1 s). A chimeric alpha7-5HT(3A) receptor exhibits functional properties intermediate between those of the parent receptors, but the functional signatures of each parent are reconstituted after substituting the major loops within the interface of the extracellular and transmembrane domains from the corresponding parent receptor. Furthermore, these structural loops contribute to open-channel lifetime and time of desensitization onset in a nonadditive manner. The results suggest that desensitization is the major determinant of the lifetimes of activated alpha7 and 5-HT(3A) receptors and that functional differences between the two receptors arise primarily through structural differences at the interface between extracellular and transmembrane domains.

SUBMITTER: Bouzat C

PROVIDER: S-EPMC3844810 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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The interface between extracellular and transmembrane domains of homomeric Cys-loop receptors governs open-channel lifetime and rate of desensitization.

Bouzat Cecilia C Bartos Mariana M Corradi Jeremías J Sine Steven M SM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080701 31

The lifetimes of activated postsynaptic receptor channels contribute to the efficiency of synaptic transmission. Here we show that structural differences within the interface dividing extracellular and transmembrane domains of homomeric alpha7 and 5-HT(3A) receptors account for the large differences in open-channel lifetime and time of desensitization onset between these contrasting members of the Cys-loop receptor superfamily. For alpha7 receptors, agonist-evoked single-channel currents appear ...[more]

PMID: 18667613

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Project description:Ivermectin is an anthelmintic drug that works by inhibiting neuronal activity and muscular contractility in arthropods and nematodes. It works by activating glutamate-gated chloride channels (GluClRs) at nanomolar concentrations. These receptors, found exclusively in invertebrates, belong to the pentameric Cys-loop receptor family of ligand-gated ion channels (LGICs). Higher (micromolar) concentrations of ivermectin also activate or modulate vertebrate Cys-loop receptors, including the excitatory nicotinic and the inhibitory GABA type-A and glycine receptors (GlyRs). An X-ray crystal structure of ivermectin complexed with the C. elegans ? GluClR demonstrated that ivermectin binds to the transmembrane domain in a cleft at the interface of adjacent subunits. It also identified three hydrogen bonds thought to attach ivermectin to its site. Site-directed mutagenesis and voltage-clamp electrophysiology have also been employed to probe the binding site for ivermectin in ?1 GlyRs. These have raised doubts as to whether the hydrogen bonds are essential for high ivermectin potency. Due to its lipophilic nature, it is likely that ivermectin accumulates in the membrane and binds reversibly (i.e., weakly) to its site. Several lines of evidence suggest that ivermectin opens the channel pore via a structural change distinct from that induced by the neurotransmitter agonist. Conformational changes occurring at locations distant from the pore can be probed using voltage-clamp fluorometry (VCF), a technique which involves quantitating agonist-induced fluorescence changes from environmentally sensitive fluorophores covalently attached to receptor domains of interest. This technique has demonstrated that ivermectin induces a global conformational change that propagates from the transmembrane domain to the neurotransmitter binding site, thus suggesting a mechanism by which ivermectin potentiates neurotransmitter-gated currents. Together, this information provides new insights into the mechanisms of action of this important drug.

Dataset Information

The interface between extracellular and transmembrane domains of homomeric Cys-loop receptors governs open-channel lifetime and rate of desensitization.

Publications

The interface between extracellular and transmembrane domains of homomeric Cys-loop receptors governs open-channel lifetime and rate of desensitization.

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