Subunit promotion energies for channel opening in heterotetrameric olfactory CNG channels

Jana Schirmeyer, Thomas Eick, Eckhard Schulz, Sabine Hummert, Christian Sattler, Ralf Schmauder and Klaus Benndorf

PLOS Computational Biology, 2022, vol. 18, issue 8, 1-22

Abstract: Cyclic nucleotide-gated (CNG) ion channels of olfactory sensory neurons contain three types of homologue subunits, two CNGA2 subunits, one CNGA4 subunit and one CNGB1b subunit. Each subunit carries an intracellular cyclic nucleotide binding domain (CNBD) whose occupation by up to four cyclic nucleotides evokes channel activation. Thereby, the subunits interact in a cooperative fashion. Here we studied 16 concatamers with systematically disabled, but still functional, binding sites and quantified channel activation by systems of intimately coupled state models transferred to 4D hypercubes, thereby exploiting a weak voltage dependence of the channels. We provide the complete landscape of free energies for the complex activation process of heterotetrameric channels, including 32 binding steps, in both the closed and open channel, as well as 16 closed-open isomerizations. The binding steps are specific for the subunits and show pronounced positive cooperativity for the binding of the second and the third ligand. The energetics of the closed-open isomerizations were disassembled to elementary subunit promotion energies for channel opening, ΔΔGfpn, adding to the free energy of the closed-open isomerization of the empty channel, E0. The ΔΔGfpn values are specific for the four subunits and presumably invariant for the specific patterns of liganding. In conclusion, subunit cooperativity is confined to the CNBD whereas the subunit promotion energies for channel opening are independent.Author summary: Olfactory sensory neurons (OSNs) in the nose transmit the information of odor molecules to electrical signals that are conducted to central parts of the brain. Olfactory cyclic nucleotide-gated (CNG) ion channels, located in the cell membrane of the OSNs, are relevant proteins in this process. These olfactory CNG channels are formed by three types of homologue subunits and each of these subunits contains a cyclic nucleotide binding domain (CNBD). A channel is activated by the binding of up to four cyclic nucleotides. The process of channel activation is only poorly understood. Herein we analyzed this activation process in great detail by concatenating these four subunits, disabling the CNBDs by mutations and performing extended computational fit analyses providing all 32 constants for the different binding steps at different degrees of liganding and, in addition, elementary subunit promotion energies for channel opening for all subunits. Our data suggest that subunit cooperativity is confined to the action of the CNBD.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1010376

DOI: 10.1371/journal.pcbi.1010376

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