Neuron
Volume 12, Issue 3, March 1994, Pages 473-482
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Coupling of CFTR Cl channel gating to an ATP hydrolysis cycle

https://doi.org/10.1016/0896-6273(94)90206-2Get rights and content

Summary

For cystic fibrosis transmembrane conductance regulator (CFTR) Cl channels to open, they must be phosphorylated by protein kinase A and then exposed to a hydrolyzable nucleoside triphosphate, such as ATP. To test whether channel opening is linked to ATP hydrolysis, we applied VO4 and BeF3 to CFTR channels in inside-out patches excised from cardiac myocytes. These inorganic phosphate analogs interrupt ATP hydrolysis cycles by binding tightly in place of the released hydrolysis product, inorganic phosphate. The analogs acted only on CFTR channels opened by ATP and locked them open, increasing their mean open time by 2–3 orders of magnitude. These findings establish that opening and closing of CFTR channels are coupled to an ATP hydrolysis cycle.

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      Citation Excerpt :

      This could explain the higher ATP sensitivities and the slower deactivation rates upon ATP removal observed for constitutive loop mutants (i.e. mutants that bias the equilibrium toward the open channel) (51). Given that the macroscopic deactivation rate of wild-type CFTR following ATP removal is determined by the rate of ATP hydrolysis and subsequent product release from site 2 (13, 14, 16, 21), the slower deactivation of these constitutive mutants (51) could be due to a slower release of ADP and/or Pi after hydrolysis. Conceptually, this can be explained by recognizing that pore opening and NBD1-NBD2 interactions are reciprocally coupled such that mutations that affect one (gating) must also bias the equilibrium toward the other (NBD dimerization).

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