Abstract
Inactivation is the process by which an open channel enters a stable
nonconducting conformation after a depolarizing change in membrane
potential. Inactivation is a widespread property of many different
types of voltage-gated ion channels. Recent advances in the molecular
biology of K$^+$ channels have elucidated two mechanistically
distinct types of inactivation, N-type and C-type. N-type inactivation
involves occlusion of the intracellular mouth of the pore through
binding of a short segment of residues at the extreme N-terminal.
In contrast to this "tethered ball" mechanism of N-type inactivation,
C-type inactivation involves movement of conserved core domain residues
that result in closure of the external mouth of the pore. Although
C-type inactivation can show rapid kinetics that approach those observed
for N-type inactivation, it is often thought of as a slowly developing
and slowly recovering process. Current models of C-type inactivation
also suggest that this process involves a relatively localized change
in conformation of residues near the external mouth of the permeation
pathway. The rate of C-type inactivation and recovery can be strongly
influenced by other factors, such as N-type inactivation, drug binding,
and changes in K$^+$o. These interactions make C-type inactivation
an important biophysical process in determining such physiologically
important properties as refractoriness and drug binding. C-type inactivation
is currently viewed as arising from small-scale rearrangements at
the external mouth of the pore. This review will examine the multiplicity
of interactions of C-type inactivation with N-terminal-mediated inactivation
and drug binding that suggest that our current view of C-type inactivation
is incomplete. This review will suggest that C-type inactivation
must involve larger-scale movements of transmembrane-spanning domains
and that such movements contribute to the diversity of kinetic properties
observed for C-type inactivation.
- 9562433
- agments,
- allosteric
- animals,
- binding,
- channel
- channels,
- fr,
- gating,
- heart,
- humans,
- ion
- membrane
- peptide
- potassium
- potentials,
- protein
- regulation,
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