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J. Gen. Physiol.,
Volume 113, Number 6, June 1, 1999 873-895
From the Department of Physiology and Biophysics, University of Colorado School of Medicine, Denver, Colorado 80262
Cyclic nucleotide-gated channels contain four subunits, each with a binding site for cGMP or cAMP
in the cytoplasmic COOH-terminal domain. Previous studies of the kinetic mechanism of activation have been
hampered by the complication that ligands are continuously binding and unbinding at each of these sites. Thus,
even at the single channel level, it has been difficult to distinguish changes in behavior that arise from a channel
with a fixed number of ligands bound from those that occur upon the binding and unbinding of ligands. For example, it is often assumed that complex behaviors like multiple conductance levels and bursting occur only as a consequence of changes in the number of bound ligands. We have overcome these ambiguities by covalently tethering one ligand at a time to single rod cyclic nucleotide-gated channels (Ruiz, ML., and J.W. Karpen. 1997. Nature. 389:389-392). We find that with a fixed number of ligands locked in place the channel freely moves between
three conductance states and undergoes bursting behavior. Furthermore, a thorough kinetic analysis of channels locked in doubly, triply, and fully liganded states reveals more than one kinetically distinguishable state at each
conductance level. Thus, even when the channel contains a fixed number of bound ligands, it can assume at least
nine distinct states. Such complex behavior is inconsistent with simple concerted or sequential allosteric models.
The data at each level of liganding can be successfully described by the same connected state model (with different rate constants), suggesting that the channel undergoes the same set of conformational changes regardless of
the number of bound ligands. A general allosteric model, which postulates one conformational change per subunit in both the absence and presence of ligand, comes close to providing enough kinetically distinct states. We
propose an extension of this model, in which more than one conformational change per subunit can occur during the process of channel activation.
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