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Marks","year":"1992","journal-title":"J Gen Physiol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1085\/jgp.200709769","article-title":"Kinetic relationship between the voltage sensor and the activation gate in spHCN channels","volume":"130","author":"A. Bruening-Wright","year":"2007","journal-title":"J Gen Physiol"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1085\/jgp.200409130","article-title":"Hysteresis in the voltage dependence of HCN channels: conversion between two modes affects pacemaker properties","volume":"125","author":"R. Mannikko","year":"2005","journal-title":"J Gen Physiol"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1113\/jphysiol.2006.110437","article-title":"Mode shifts in the voltage gating of the mouse and human HCN2 and HCN4 channels","volume":"575","author":"F. 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