Evidence that CFTR Channels Can Regulate the Open Duration of other CFTR Channels: Cooperativity

Abstract.

CFTR channels mediate secretion and absorption in epithelia, and cystic fibrosis is caused by their malfunction. CFTR proteins are members of the ABC transporter family and are complexly regulated by phosphorylation and nucleosides; they also influence other channel activity. Do CFTR molecules also influence one another? Cooperativity has been observed among other channels and has been suggested for CFTR. Therefore, we looked for evidence of cooperativity among CFTR channels using three independent approaches. All three methods provided evidence for cooperativity in CFTR gating. We estimated mean open times, independent of the number of channels in the patch, in multi-channel patches and showed that, on average, they increased as channel number increased. We observed many trials having larger than expected variances, consistent with cooperative gating. We also measured deviations from binomial statistics, which revealed cooperativity and further indicated that its magnitude is underestimated to an unknown extent because of masking that occurs when CFTR channel populations within a single patch have heterogeneous open probabilities. Simulations showed that the observed departures from binomial statistics were too large to have arisen by chance. The evidence that CFTR P(o) increases with channel density has important functional implications.