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NEUROKCNQPATHIES Sintesi della relazione

Project ID: 503038
Finanziato nell'ambito di: FP6-LIFESCIHEALTH
Paese: Spain

Final Report Summary - NEUROKCNQPATHIES (Cell biology of rare monogenic neurological disorders involving kcnq channels)

This project focused on unravelling the cell biology underlying rare monogenic neurological disorders associated with KCNQ family members by identifying the processes that control KCNQ channel function, including their modulation by second messengers, biogenesis, targeting and transcriptional control. It also aimed to identify and characterise the mode of action of new drugs that affect the function of these channels.

As part of the project the team analysed the biochemical and biophysical properties of the mutations associated with these disorders. Structure-function studies were undertaken to unveil the processes affected, including the trafficking, membrane insertion, assembly (oligomerisation) and degradation of KCNQ channels. The transduction mechanisms underlying their regulation by neurotransmitters were also studied. By exploring protein-protein interactions, the molecular complexes that interact with these channels were deciphered, and the physiological significance of the interactions identified and validated was analysed.

Because some mutations in the KCNQ loci do not appear to lie in the coding region, and nothing is known about the control of KCNQ gene transcription, the team also studied how the expression of those genes is regulated. Mouse models for some of the disorders were available for analysis in this project, however further conditional mutants were also produced to gain a more precise idea of the pathology of these diseases. Mutagenesis structure-function studies also unveiled the molecular basis for drug specificity, permitting the mechanisms of action to be defined. We have already found new drugs that modulate KCNQ channels with promising pharmacological potential and we will continue to screen for new compounds using high throughput methods, evaluating their therapeutic potential.

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Capus Universitari, 08193 Cerdanyola del Vallès