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Structure-function properties of pac...

Xue, Tian.

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Structure-function properties of pacemaker channels.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Structure-function properties of pacemaker channels./
Author:	Xue, Tian.
Description:	179 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-12, Section: B, page: 6131.
Contained By:	Dissertation Abstracts International65-12B.
Subject:	Biology, Animal Physiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3155714
ISBN:	0496165208

Structure-function properties of pacemaker channels.
Xue, Tian.

Structure-function properties of pacemaker channels. - 179 p.

Source: Dissertation Abstracts International, Volume: 65-12, Section: B, page: 6131.

Thesis (Ph.D.)--The Johns Hopkins University, 2005.

HCN-encoded If, a diastolic depolarizing current activated by hyperpolarization, is a key player in cardiac pacing. Although HCN channels structurally resemble voltage-gated K+ (Kv) channels structurally, two distinct features set them apart from each other: HCN channels are (1) non-selective and (2) gated by opposite voltages. The molecular features underlying these phenotypic differences are unknown. Here I investigated the structure-function properties of HCN channels using various molecular and electrophysiological techniques. Since the HCN pore contains the signature motif (GYG) found in almost all K+-selective channels, I first probed the functional importance of the ionic selectivity filter of HCN channels by replacing this triplet with alanines (HCN1GYG349-351AAA). My results provide the first experimental evidence that HCN channels are tetramers. Using hydrophilic sulfhydryl modifiers (MTS), I next identified an externally-accessible endogenous cysteine, C318, that resides in a pore region that may undergo significant gating-induced dynamic rearrangements. Consistent with this notion, I further demonstrated that external permeant ions can modulate HCN gating in an isoform-specific manner. This effect can be abolished by the single pore substitution A352D. To obtain further insights into HCN gating, I next switched my focus to the voltage sensor. My results led me to propose a novel double-hinge model for the paradoxical gating behavior of HCN channels. The model exemplifies the economics of evolution: HCN and Kv channels have similar overall designs but relatively subtle structural changes suffice to result in vast phenotypic differences.

ISBN: 0496165208Subjects--Topical Terms:

1017835
Biology, Animal Physiology.

Structure-function properties of pacemaker channels.
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245 1 0 $a Structure-function properties of pacemaker channels.
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500 $a Source: Dissertation Abstracts International, Volume: 65-12, Section: B, page: 6131.
500 $a Adviser: Eduardo Marban.
502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2005.
520 $a HCN-encoded If, a diastolic depolarizing current activated by hyperpolarization, is a key player in cardiac pacing. Although HCN channels structurally resemble voltage-gated K+ (Kv) channels structurally, two distinct features set them apart from each other: HCN channels are (1) non-selective and (2) gated by opposite voltages. The molecular features underlying these phenotypic differences are unknown. Here I investigated the structure-function properties of HCN channels using various molecular and electrophysiological techniques. Since the HCN pore contains the signature motif (GYG) found in almost all K+-selective channels, I first probed the functional importance of the ionic selectivity filter of HCN channels by replacing this triplet with alanines (HCN1GYG349-351AAA). My results provide the first experimental evidence that HCN channels are tetramers. Using hydrophilic sulfhydryl modifiers (MTS), I next identified an externally-accessible endogenous cysteine, C318, that resides in a pore region that may undergo significant gating-induced dynamic rearrangements. Consistent with this notion, I further demonstrated that external permeant ions can modulate HCN gating in an isoform-specific manner. This effect can be abolished by the single pore substitution A352D. To obtain further insights into HCN gating, I next switched my focus to the voltage sensor. My results led me to propose a novel double-hinge model for the paradoxical gating behavior of HCN channels. The model exemplifies the economics of evolution: HCN and Kv channels have similar overall designs but relatively subtle structural changes suffice to result in vast phenotypic differences.
590 $a School code: 0098.
650 4 $a Biology, Animal Physiology. $3 1017835
650 4 $a Chemistry, Biochemistry. $3 1017722
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