A historical biophysical dogma vs. an understanding of the structure and function of voltage-gated tetrameric ion channels. A review

• Published in: Biochimica et biophysica acta. Biomembranes 2022-12, Vol.1864 (12), p.184046-184046, Article 184046
• Main Author: Guidelli, Rolando
• Format: Article
• Language: English
• Subjects: Hodgkin and Huxley parametrization; Markov stochastic models; Shaker potassium channel; Sodium channel; T-type calcium channel; Voltage-gated tetrameric ion channels
• ISSN: 0005-2736; 1879-2642
• DOI: 10.1016/j.bbamem.2022.184046

The outstanding work of several eminent biophysicists has allowed the functional features of voltage-gated tetrameric ion channels to be disclosed using ingenious and sophisticated electrophysiological techniques. However, the kinetics and mechanism underlying these functions have been heavily conditioned by an arbitrary interpretation of the groundbreaking results obtained by Hodgkin and Huxley (HH) in their investigation of sodium and potassium currents using the voltage clamp technique. Thus, the heavy parametrization of their results was considered to indicate that any proposed sequence of closed states terminates with a single open state. This ‘dogma’ of HH parametrization has influenced the formulation of countless mechanistic models, mainly stochastic, requiring a high number of free parameters and of often unspecified conformational states. This note aims to point out the advantages of a deterministic kinetic model that simulates the main features of tetrameric ion channels using only two free parameters by assuming their stepwise opening accompanied by a progressively increasing cation flow. This model exploits the electrostatic attractive interactions stemming from the charge distribution shared by all tetrameric ion channels, providing a close connection between their structure and function. Quite significantly, a stepwise opening of all ligand-gated tetrameric ion channels, such as glutamate receptors (GluRs), with concomitant ion flow, is nowadays generally accepted, not having been influenced by this dogma. This provides a unified picture of both voltage-gated and ligand-gated tetrameric ion channels. [Display omitted] •A biophysical dogma hypothesizes a single final open state in tetrameric ion channels.•This dogma relies on an unjustified interpretation of Hodgkin-Huxley parametrization.•This dogma yields ion channel stochastic models with more than nine free parameters.•Stepwise gating charges induce stepwise opening of the activation gate of ion channels.•Models assuming stepwise opening of the activation gate require two free parameters.