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Emerging Concepts in Ion Channel Biophysics
Wednesday Speaker Abstracts
21
Molecular Mechanisms of Regulation of Ion Channels by Intracellular Domains
William N. Zagotta
.
University of Washington, Seattle, WA, USA.
The family of cyclic nucleotide-binding domain (CNBD)-containing ion channels includes CNG,
HCN, and KCNH channels. While these channels all contain a C-linker and CNBD in their
carboxy-terminal region and are structurally very similar, they are functionally quite diverse.
Their ion selectivity ranges from strongly potassium selective (KCNH) to weakly potassium
selective (HCN) to cation nonselective (CNG), and their voltage-dependence ranges from
depolarization activated (KCNH) to hyperpolarization activated (HCN) to voltage independent
(CNG). In addition, while the CNG and HCN channels are activated by the direct binding of
cyclic nucleotide, the KCNH channels do not bind and are not regulated by cyclic nucleotides.
Using a combination of X-ray crystallography and electrophysiology we have shown that this
lack of regulation of KCNH channels by cyclic nucleotide is because the would-be binding
pocket of KCNH channels is occupied by a segment of the channel itself, we call the intrinsic
ligand. Furthermore, we have shown that the cyclic nucleotide-binding homology domain
(CNBHD) of KCNH channels directly interacts with the amino-terminal eag domain of these
channels. Recently, using a combination of transition metal ion FRET (tmFRET), patch-clamp
fluorometry (PCF), and a fluorescent noncanonical amino acid (Anap), we have shown that there
is a slow rearrangement of the eag domain/CNBHD interaction associated with the voltage-
dependent activation of KCNH channels. This rearrangement produces a large voltage-dependent
potentiation of the channel, similar to prepulse facilitation in other channels, which is thought to
regulate cardiac and neuronal excitability. We propose that instead of cyclic nucleotide-
regulation, the CNBHD of KCNH channels has evolved to produce voltage-dependent
potentiation.