title: A data-driven model of a modal gated ion channel: the inositol 1,4,5-trisphosphate receptor in insect Sf9 cells.
abstract: The inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) channel is crucial for the generation and modulation of intracellular Ca(2+) signals in animal cells. To gain insight into the complicated ligand regulation of this ubiquitous channel, we constructed a simple quantitative continuous-time Markov-chain model from the data. Our model accounts for most experimentally observed gating behaviors of single native IP(3)R channels from insect Sf9 cells. Ligand (Ca(2+) and IP(3)) dependencies of channel activity established six main ligand-bound channel complexes, where a complex consists of one or more states with the same ligand stoichiometry and open or closed conformation. Channel gating in three distinct modes added one complex and indicated that three complexes gate in multiple modes. This also restricted the connectivity between channel complexes. Finally, latencies of channel responses to abrupt ligand concentration changes defined a model with specific network topology between 9 closed and 3 open states. The model with 28 parameters can closely reproduce the equilibrium gating statistics for all three gating modes over a broad range of ligand concentrations. It also captures the major features of channel response latency distributions. The model can generate falsifiable predictions of IP(3)R channel gating behaviors and provide insights to both guide future experiment development and improve IP(3)R channel gating analysis. Maximum likelihood estimates of the model parameters and of the parameters in the De Young-Keizer model yield strong statistical evidence in favor of our model. Our method is simple and easily applicable to the dynamics of other ion channels and molecules.
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87544, USA.
authors.forename: Ghanim
authors.initials: G
authors.lastname: Ullah
authors.forename: Don-On Daniel
authors.initials: DO
authors.lastname: Mak
authors.forename: John E
authors.initials: JE
authors.lastname: Pearson
mesh_terms: D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000737:chemistry / Q000378:metabolism*; D015640:Ion Channel Gating; D007700:Kinetics; D008024:Ligands; D008959:Models, Neurological; D011487:Protein Conformation; D061987:Sf9 Cells; D018411:Spodoptera
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium