Journal article
Free-energy relationships in ion channels activated by voltage and ligand
The Journal of general physiology, Vol.141(1), pp.11-28
01/01/2013
DOI: 10.1085/jgp.201210860
PMCID: PMC3536522
PMID: 23250866
Abstract
Many ion channels are modulated by multiple stimuli, which allow them to integrate a variety of cellular signals and precisely respond to physiological needs. Understanding how these different signaling pathways interact has been a challenge in part because of the complexity of underlying models. In this study, we analyzed the energetic relationships in polymodal ion channels using linkage principles. We first show that in proteins dually modulated by voltage and ligand, the net free-energy change can be obtained by measuring the charge-voltage (Q-V) relationship in zero ligand condition and the ligand binding curve at highly depolarizing membrane voltages. Next, we show that the voltage-dependent changes in ligand occupancy of the protein can be directly obtained by measuring the Q-V curves at multiple ligand concentrations. When a single reference ligand binding curve is available, this relationship allows us to reconstruct ligand binding curves at different voltages. More significantly, we establish that the shift of the Q-V curve between zero and saturating ligand concentration is a direct estimate of the interaction energy between the ligand-and voltage-dependent pathway. These free-energy relationships were tested by numerical simulations of a detailed gating model of the BK channel. Furthermore, as a proof of principle, we estimate the interaction energy between the ligand binding and voltage-dependent pathways for HCN2 channels whose ligand binding curves at various voltages are available. These emerging principles will be useful for high-throughput mutagenesis studies aimed at identifying interaction pathways between various regulatory domains in a polymodal ion channel.
Details
- Title: Subtitle
- Free-energy relationships in ion channels activated by voltage and ligand
- Creators
- Sandipan Chowdhury - Graduate Program in Biophysics andBaron Chanda - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- The Journal of general physiology, Vol.141(1), pp.11-28
- DOI
- 10.1085/jgp.201210860
- PMID
- 23250866
- PMCID
- PMC3536522
- NLM abbreviation
- J Gen Physiol
- ISSN
- 0022-1295
- eISSN
- 1540-7748
- Publisher
- Rockefeller Univ Press
- Number of pages
- 18
- Grant note
- Shaw Scientist award R01NS081293 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) R01GM084140 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) GM084140 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 01/01/2013
- Academic Unit
- Molecular Physiology and Biophysics
- Record Identifier
- 9984297612502771
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