Ion Channels of Excitable Membranes

Ion Channels of Excitable Membranes,
by Bertil Hille.

In Intermediate Physics for Medicine and Biology, Russ Hobbie and I claim

“The classic monograph on ion channels is the book by Hille (2001).”

Not only is Bertil Hille’s book Ion Channels of Excitable Membranes a classic, but also it’s extraordinarily well written. To learn about ion channels, read this book. The introduction begins eloquently

Ion channels are macromolecular pores in cell membranes. When they evolved and what role they may have played in the earliest forms of life we still do not know, but today ion channels are most obvious as the fundamental excitable elements in the membranes of excitable cells. Ion channels bear the same relation to electrical signaling in nerve, muscle, and synapse as enzymes bear to metabolism. Although their diversity is less broad than that of enzymes, there are still many types of channels working in concert, opening and closing to shape the signals and responses of the nervous system. Sensitive but potent amplifiers, they detect the sounds of chamber music and guide the artist’s paintbrush, yet also generate the violent discharges of the electric eel or the electric ray. They tell the Paramecium to swim backward after a gentle collision, and they propagate the leaf-closing response of the Mimosa plant.

Hille appreciates the role of physics in electrophysiology.

More than in most areas of biology, we see in the study of ion channels how much can be learned by applying simple laws of physics. Much of what we know about ion channels is deduced from electrical measurements. Therefore it is essential to remember some rules of electricity…

Let’s look at some topics covered by both IPMB and ICEM.
Russ and I briefly mention toxins, saying “an example is tetrodotoxin (TTX), which binds to sodium channels and blocks them, making it a deadly poison.” Hille goes into more detail, explaining how toxins help separate currents and identify channels.

Pharmacological experiments with [channel blocking toxins] provided the first evidence needed to define channels as discrete entities. The magic bullet was tetrodotoxin (dubbed TTX by K.S. Cole), a paralytic poison of some puffer fish… In Japan this potent toxin attracted medical attention because puffer fish is prized there as a delicacy — with occasional fatal effects. Tetrodotoxin blocks action potential conduction in nerve and muscle. Toshio Narahashi brought a sample of TTX to John Moore’s laboratory in the United States. Their first voltage-clamp study with lobster giant axons revealed that TTX blocks INa [the sodium current] selectively, leaving IK and IL [the potassium and leak currents] untouched… Only nanomolar concentrations were needed.

Russ and I continue “the next big advance was patch-clamp recording…[which] revealed that the [ion channel] pores open and close randomly.” Hille expands on this idea.

Patch clamp … forced a revision of the kinetic description of channel gating. At the single-channel level, the gating transitions are stochastic: they can be predicted only in terms of probabilities. Each trial with the same depolarizing step shows a new pattern of openings! Nevertheless, as Hodgkin and Huxley showed, gating does follow rules… Brief openings of Na channels are induced by repeated depolarizing steps… The openings appear after a short delay and cluster early in the sweep. When many records like this are averaged together, the ensemble average has a smoother transient time course of opening and closing, resembling the classical activation-inactivation sequence for macroscopic INa.

Hille’s Figures 3.16 and 3.17 — showing many individual patch clamp recordings averaged to reproduce the macroscopic Hodgkin and Huxley sodium and potassium currents — are my favorite illustrations in ICEM.
Russ and I have one paragraph about calcium channels. Hille has a whole chapter.

The biophysical properties of Ca channels might have been determined by classical voltage-clamp methods if the channels occurred in high density on a reliably clampable membrane. However, these channels are never found in high density, and many of the interesting ones occupy membranes that are difficult to clamp, such as dendrites, nerve terminals, and the complex infoldings of muscle cells. Even when Ca channels are on the surface membranes, as in the cell bodies of neurons, their small currents tend to be masked by those of many other channels, especially K [potassium] channels. The ambiguities caused by these problems delayed biophysical understanding of Ca channels.

Russ and I relegate inward rectification to a homework problem. Hille discusses why inward rectifiers are important.

Axons seem to be built for metabolic economy at rest. At the negative resting potential, all their channels tend to shut, minimizing the flow of antagonistic inward and outward currents and minimizing the metabolic costs of idling. Depolarization, on the other hand, tends to open channels and dissipate ion gradients, but the inactivation of Na channels and the delayed activation of K channels in axons keeps even this expenditure at a minimum.

Consider, however, the electrical activity of a tissue that cannot rest: the heart… Its cells spend almost half their time in the depolarized state… Furthermore, each depolarization lasts 100–600 ms. Metabolic economy in this busy but slow electrical activity is achieved in two ways. First, most ion channels are present at very low densities in heart cells, so even when activated, they pass [only small] currents…

The second economy, in non-pacemaker cells of the heart, is a type of K channel, the inward rectifier, that stops conducting during depolarization. The total membrane conductance is actually lower during the plateau phase of such action potentials than during the period between action potentials… Again antagonistic current flows are minimized. Heart muscle has a variety of K channels, many of which have the property of inward rectification or of rapid inactivation.

Other topics covered in both IPMB and ICEM are Roderick MacKinnon’s study of the structure of the potassium channel, and the Hodgkin and Huxley model for the action potential in a squid axon. Having coauthored a textbook, I appreciate how much work must have gone into writing Ion Channels of Excitable Membranes.

  • The figures are all clear, drawn in a uniform style, with a focus on the data. To have a consistent look, you can’t just cut and paste figures from an article into a book. They had to be lovingly reproduced and reformatted.
  • The list of references contains about 1800 articles summarizing the literature up to 2001, the date of the most recent edition.
  • The language is clear and readable. Young scientists looking for an example of effective scientific writing should read ICEM.
  • Hille appreciates the history of his subject. Concepts are clearer when placed in historical context.
  • The book is authoritative because the author is a giant in his field. He received the Lasker award (America’s Nobel) for his work on ion channels.
  • I would compare ICEM to the robust hybrid offspring of a marriage between Solid State Physics (Ashcroft and Mermin) and Nerve, Muscle, and Synapse (Katz).

Intermediate Physics for Medicine and Biology is superior to Ion Channels of Excitable Membranes in one way: homework problems. ICEM has none and IPMB has hundreds.

Originally published at on March 15, 2019.

Professor of Physics at Oakland University and coauthor of the textbook Intermediate Physics for Medicine and Biology.