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May 2014

Finding the correct target to aim at in Animal Health Drug Discovery

PLoS One 9(5): e97468

In recent years it has become clear that natural polymorphisms, RNA editing and alternative splicing can result in a substantial variety of expressed forms of a gene encoding a neurotransmitter receptor subunit. These variants can impact on the actions of the neurotransmitter and may play important roles in modulating signal traffic between neurons and thereby influencing neural circuits. They can also impact on the actions of drugs and chemicals targeting those receptors.

Receptors for the neurotransmitter γ-aminobutyric acid (GABA) gate chloride channels and are fundamental to inhibitory signalling processes. Insect GABA receptors are also the targets for several classes of current insecticides, including fipronil.  The RDL (resistance to dieldrin) GABA receptor, originally isolated from Drosophila melanogaster undergoes alternative splicing and RNA editing, which can influence the potency of GABA.  Most work to date has focussed on minority isoforms.

Recently, work in the Sattelle laboratory at University College London, along with their collaborators in The University of Oxford (Biochemistry), and The University of Manchester (Life Sciences) resulted in the first characterisation of the predominant native splice variant and RNA edit, of RDL. The authors combined functional characterisation with pharmacology, molecular modelling of the agonist-binding region.  The importance of targeting the predominant form of the receptor as opposed to a minority isoform could have important implications in the design of effective, safe chemicals for use in maintaining animal health.

September 2012

Worm models assist in fronto-temporal lobe dementia research

C9ORF72 Steals the Show at Frontotemporal Dementia Meeting