Binding and structural asymmetry governs ligand sensitivity in a cyclic nucleotide–gated ion channel

Author:

Ng Leo C.T.1,Zhuang Meiying1,Van Petegem Filip2ORCID,Li Yue Xian3,Accili Eric A.1ORCID

Affiliation:

1. Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada

2. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada

3. Department of Mathematics, University of British Columbia, Vancouver, BC, Canada

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open more easily when cAMP or cGMP bind to a domain in the intracellular C-terminus in each of four identical subunits. How sensitivity of the channels to these ligands is determined is not well understood. Here, we apply a mathematical model, which incorporates negative cooperativity, to gating and mutagenesis data available in the literature and combine the results with binding data collected using isothermal titration calorimetry. This model recapitulates the concentration–response data for the effects of cAMP and cGMP on wild-type HCN2 channel opening and, remarkably, predicts the concentration–response data for a subset of mutants with single-point amino acid substitutions in the binding site. Our results suggest that ligand sensitivity is determined by negative cooperativity and asymmetric effects on structure and channel opening, which are tuned by ligand-specific interactions and residues within the binding site.

Funder

Canadian Institutes of Health Research

Natural Sciences and Engineering Research Council of Canada

Canada Research Chair

Publisher

Rockefeller University Press

Subject

Physiology

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