2 S. A. Pless and C. A. Ahern
implications of ion channel function on physiological processes are vast. Electri-
cal impulses, in the form of action potentials or diverse chemo-electrical signals,
coordinate the syncytium of the heart beat, support a myriad of neuronal commu-
nication pathways, insulin secretion, and are central to the immune response, with
more roles being discovered virtually everyday. Thus, ion channel function is a
biophysical process that is central to biological life at many levels. And with over
500 channel-forming subunits known today in humans, this large class of proteins is
also increasingly recognised as important drug targets, as inherited or acquired ion
channel dysfunction are known causes of disease.
Many ion channels are ‘selective’, i.e. they display a strong preference (or selec-
tivity) for either a cations or anions, or even for a certain type of cation, e.g. potas-
sium ions. Depending on the type of ion channel the activity of these proteins is
controlled (or gated) by a wide variety of stimuli, including chemical, electrical and
physical: while many ion channels open in response to binding of ligands to (ligand-
gated ion channels), others do so as a result of changes in the membrane (voltage-
gated ion channels) or even mechanical stimuli (mechanosensitive channels). In-
terestingly, it is becoming more and more clear that a number of ion channel types
are responsive to more than one stimuli, resulting in a polymodal gating behaviour.
The study of ion channels has been traditionally challenging and the field re-
quired numerous major technological advances to blossom to its current state of
understanding. Although the idea of bioelectricity had been formulated as early
1786 by Galvani, the molecular and atomic basis for this phenomenon remains
surprisingly elusive. A seminal breakthrough, both conceptual and technical,
came about in the in the mid-twentieth century when Hodgkin and Huxley estab-
lished the ability to record ionic currents from the quid giant axon. Soon after,
this led to the pioneering work of Sakmann and Neher who established the patch
clamp technology, which allows measurement of the unitary ionic currents in the
picoampere range. Later on, the purification and cloning of membrane protein
(complexes) delivered the first protein sequences of ion channels and transmem-
brane receptor proteins. Of crucial importance in this context was the develop-
ment of the polymerase chain reaction (PCR), which facilitated gene cloning, but
also endowed researchers with the capability to change the coding frame of ion
channels. This molecular revolution segued to the high-resolution crystal struc-
tures of channels by the MacKinnon and Agre laboratories, which has harkened
a new era of atomic scale understanding that continues to surprise and illuminate
the ion channel world. Thus at each step in the conceptual, molecular and atomic
understanding of bioelectricity in animals; from the spark of life, to macroscopic
and microscopic ionic recordings, and then molecular expression, site-directed
mutagenesis and structural biology, crucial technological innovations and their
subsequent widespread application has been the common (and essential) driver
in progress.
Indeed, the efforts over the past 25 years through the combination of structural
and functional interrogation of ion channel genes has been an incredibly powerful
means to elucidate the physiology and pharmacology of ion channels. However,