The CFTR protein, when mutated, causes the disease cystic fibrosis/mucoviscidosis (herein referred to as CF). However, the severity of CF disease, its time of presentation and its organ damaging potential all vary so much that a new paradigm is needed beyond the out-moded idea that CF is merely a recessive disease. Indeed carrying just one mutation is no longer thought to be benign as such patients are present in great excess in a variety of hospital clinics specialising in infertility, GI cancer, bronchiectasis and nasal polyposis. This suggests a quasi-dominant role for mutated CFTR (heterozygote advantage discussed in Mehta in Lancet, audio- archive section podcast, 2010). Thus CF is a ‘leaky’ recessive disease with a failure to resolve inflammation and multiply dysfunctional ion channels at its root(s). Their relative roles are not agreed. My group's approach to understand this variability asks not what controls the wild type and mutant proteins. Quite the reverse. We ask instead what the CFTR protein controls and how it controls multiple cell signalling systems through two different types of protein and nucleotide phosphorylation – phosphohistidine, nucleotide generation and phosphoserine. Thus our approach asks what else does this ion channel do apart from moving ions passively according to an electrochemical driving force? Our data suggests that CFTR acts as a multi-kinase controller anchored to the membrane providing a membrane-delimited signalosome. Furthermore, in Tosoni et al, Biochem J 2013, we link the destruction of CFTR to this kinase (mis)control suggesting that fragments of CFTR bearing the site of the common mutation act as allosteric kinase controllers towards a protein kinase with hundreds of targets, kinase CK2 (casein kinase 2).

In cell attached patches, David Sheppard from Bristol and others find that CFTR is quiescent at rest, with occasional open bursts that rapidly terminate. In this seminar, the idea that two protein kinases that normally combine their actions to achieve this basal closure will be expanded with our recent data from our partners in Regensburg, Melbourne and Pittsburgh showing how these proteins interact with each other across model systems. In this respect, because the kinases belong to different ‘energetic universes’ , the work to be presented has echoes of the chicken and egg debate from the last century that explored the relationship between (high energy) phospho-histidine and oxidative phosphorylation of ATP in mitochondrial function.