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Molecular determinants of channel function
1Department of Physiology and Biophysics, Cornell University Medical College, New York, New York.
Insights
The Hodgkin-Huxley model
Area of Science:
- Cellular Electrophysiology
- Molecular Neuroscience
- Biophysics
Background:
- The Hodgkin-Huxley model, proposed 40 years ago, accurately described electrical excitability using voltage-dependent changes.
- This framework remains robust, integrating molecular insights into ion channels.
- Advancements in molecular biology and electrophysiology have validated and expanded upon the original model.
Purpose of the Study:
- To review the progress in understanding the molecular basis of electrical activity since the Hodgkin-Huxley papers.
- To highlight the impact of new technologies like patch clamp and protein sequencing on channel research.
- To outline future directions in deciphering high-resolution channel structures and functions.
Main Methods:
- Review of seminal papers and subsequent research in cellular electrophysiology.
- Integration of molecular biology techniques, including protein sequencing and structural analysis.
- Application of electrophysiological measurements (e.g., patch clamp) to study ion channel function.
Main Results:
- Voltage- and ligand-dependent ion channels are now the established framework for cellular electrophysiology.
- Giga-seal patch clamp and protein sequencing have revolutionized the study of ion channel structure and activity.
- Progress has been made in understanding ion conductance and selectivity at the molecular level.
Conclusions:
- The Hodgkin-Huxley model's core principles are validated by molecular understanding of ion channels.
- Future research will focus on high-resolution structural determination and understanding complex gating mechanisms.
- A molecular understanding of ion permeation and gating relies on fundamental principles of intermolecular forces.
Abstract:
The 40 years since the seminal papers of Hodgkin and Huxley appeared have been extraordinarily productive in terms of understanding the molecular basis for electrical activity. The Hodgkin-Huxley proposal that electrical excitability should be understood in terms of voltage-dependent changes in discrete sites has been resoundingly verified. Indeed, the Hodgkin-Huxley framework is remarkable in that its essential elements have remained largely intact as molecular understanding has advanced. This robustness is, at least in part, a result of the fact that Hodgkin and Huxley developed a mathematical model, based on simple physical arguments, that was sufficiently comprehensive to describe the kinetics of the voltage-clamped currents and yet simple enough to be predictive. The predictive features were demonstrated early by the reconstruction of both space-clamped and propagated action potentials on a desk-top calculator (293) and, later, when the sites of Hodgkin and Huxley developed into being well-characterized molecular structures. Voltage- and ligand-dependent ion-selective channels are now the established framework within which cellular electrophysiology is being pursued. Moreover, electrophysiological measurements of membrane and single-channel currents have become essential tools to examine molecular questions pertaining to channel structure and activity. The last 10 years have witnessed spectacular activity, which has resulted from two developments, the giga-seal patch clamp (249) and the elucidation of primary sequences of a number of channel-forming proteins (494), along with the first outlines of their low-resolution three-dimensional structures (651). The stage is now set for 1) applying a variety of convergent techniques to decipher molecular structural details at high resolution, and 2) seeking to understand the complex dynamic functions, gating, and ion selectivity at the molecular level. The early successes are likely to be in understanding the molecular determinants of ion conductance and selectivity, initially in terms of quantitative descriptions of how a sequence modification can alter a channel's permeability characteristics. Channel gating is a far more elusive target because it involves molecular rearrangements, which are poorly understood at any level of description and which may be modified by the channel's environment. The general mechanisms of ion permeation and gating will differ among different classes of ion channels, but a molecular understanding of either phenomenon must eventually be based on an understanding of intermolecular forces, which are invariant among all channel types.(ABSTRACT TRUNCATED AT 400 WORDS)