Spontaneous mutations in three of the five known KCNQ family members are associated with rare monogenic neurological disorders including a novel rare neurological disorder linked to mental retardation. This project will focus on unravelling the cell biology underlying these disorders by identifying the processes that control KCNQ channel function, including their modulation by second messengers, biogenesis, targeting and transcriptional control. We shall identify and characterise the mode of action of new drugs that affect the function of these channels.

We will analyse the biochemical and biophysical properties of the mutations associated with these disorders. Structure-function studies will unveil the processes affected, including the trafficking, membrane insertion, assembly (oligomerisation) and degradation of KCNQ channels. The transduction mechanisms underlying their regulation by neurotransmitters will be studied. By exploring protein-protein interactions, the molecular complexes that interact with these channels will be deciphered, and the physiological significance of the interactions identified and validated will be 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, we will study how the expression of those genes is regulated. Mouse models for some of the disorders are available for analysis in this project, and further conditional mutants will be produced to gain a more precise idea of the pathology of these diseases. Mutagenesis structure-function studies will also unveil 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 screen for new compounds using high throughput methods, evaluating their therapeutic potential.