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Structure, gating and modulation of ...

Chen, Shan.

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Structure, gating and modulation of hyperpolarization-activated HCN pacemaker channels.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Structure, gating and modulation of hyperpolarization-activated HCN pacemaker channels./
作者:	Chen, Shan.
面頁冊數:	134 p.
附註:	Source: Dissertation Abstracts International, Volume: 63-03, Section: B, page: 1213.
Contained By:	Dissertation Abstracts International63-03B.
標題:	Biophysics, General. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3048109
ISBN:	0493623833

Structure, gating and modulation of hyperpolarization-activated HCN pacemaker channels.
Chen, Shan.

Structure, gating and modulation of hyperpolarization-activated HCN pacemaker channels. - 134 p.

Source: Dissertation Abstracts International, Volume: 63-03, Section: B, page: 1213.

Thesis (Ph.D.)--Columbia University, 2002.

The hyperpolarization-activated pacemaker channels are encoded by the recently identified HCN gene family. These gene products generate non-specific cation currents (Ih) that underlie periodic electrical activity in brain and heart. In this thesis, I studied the gating properties of the HCN pacemaker channels.

ISBN: 0493623833Subjects--Topical Terms:

1019105
Biophysics, General.

Structure, gating and modulation of hyperpolarization-activated HCN pacemaker channels.
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502 $a Thesis (Ph.D.)--Columbia University, 2002.
520 $a The hyperpolarization-activated pacemaker channels are encoded by the recently identified HCN gene family. These gene products generate non-specific cation currents (Ih) that underlie periodic electrical activity in brain and heart. In this thesis, I studied the gating properties of the HCN pacemaker channels.
520 $a I first characterized the biophysical properties of two isoforms, HCN1 and HCN2. When expressed in Xenopus oocytes, HCN1 channels require less hyperpolarization to activate and open more rapidly than HCN2 channels. In cell-free patches, the steady-state activation curve of HCN1 shows a smaller shift in response to cAMP compared with that of HCN2. Next, I assessed the possibility that HCN1 and HCN2 coassemble to form heteromultimers with unique properties. Coexpression of HCN1 and HCN2 yields Ih currents with novel activation kinetics, voltage dependence and cAMP modulation, which cannot be reproduced by the linear sum of independent populations of HCN1 and HCN2 homomers, suggesting the formation of heteromeric channels with distinct properties. I also found that Ih is modulated by basal levels of cAMP in intact oocytes, according to a cyclic allosteric model. In this model, cAMP binding to the HCN channels is coupled to opening so that cAMP binds with much higher affinity to the open state of the channel than to the closed state. In the presence of a subsaturating concentration of cAMP, the model predicts a slow component in HCN channel activation kinetics due to the slow, high affinity binding of cAMP to channels once they have opened. The model accounts for both qualitative and quantitative aspects of channel kinetics. The likely physiological significance of this slow component of HCN activation was demonstrated using a computer simulation of a thalamacortical relay neuron. My findings therefore demonstrate a novel regulatory mechanism by which cAMP alters cellular function through activity-dependent changes in cAMP binding to its target, the HCN channels, rather than through changes in the intracellular concentration of cAMP. These results help elucidate the mechanisms of how HCN channels gate and are modulated to serve their pacemaking functions.
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