UBC Theses and Dissertations
A kinetic model for the HCN2 ion channel Kim, Jae Gak
The focus of my investigation is the hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel, also known as the pacemaker channel. There are four mammalian isoforms (HCN1-HCN4) that share about 60% sequence identity with each other, all activated by hyperpolarization of the membrane potential and permeable to both potassium and sodium. The major differences among four isomers are their responses to binding of cyclic adenosine monophosphate (cAMP), the rate of channel opening and closing, and their dependence on voltage. Recent studies have suggested that the opening and closing of HCN channels involve a step that is voltage independent, which depends upon a region that resides within the S4 and S6 transmembrane region. My study is based upon recent data from the Accili lab in which substitution of a phenylalanine (F) residue near the inner activation gate of the HCN2 channel to alanine (A) dramatically and preferentially slows down channel closing and decreases the dependence of closing on voltage. A 6-state, but not a 4-state, cyclic allosteric model incorporating voltage-dependent transitions moving the channels between resting and active states and voltage-independent transitions between closed and open states was able to describe the complex opening and closing of both the wild type and F/A mutant channels in response to changes in voltage. These models also predicted a significant opening probability between the open and closed states when the channel resides in the resting state.
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