Biomedical Engineering Reference
In-Depth Information
13.1.4 M
OLECULAR
S
TRUCTURES
OF
I
ON
C
HANNELS
Ion channels are present in all cells, and these naturally occurring channels have been extensively
characterized with respect to gating kinetics, voltage- and ligand-sensitivity, pharmacology, and
other parameters. In addition many ion channel types exhibit high afi nity (pM or nM) to a number
of toxins derived from scorpions, snakes, snails, or other animals, so toxins have been widely used
to differentiate between the channels subtypes. The overall parameter used when describing an ion
channel is its selectivity, i.e., whether it is selective to permeation of K
+
, Na
+
, Ca
2+
, or Cl
−
. Some
channels are nonselective among cations. Since the selectivity is tightly coupled to the physiological
function of the channels, this division is pragmatic and will be used in this chapter.
Following the sequencing of the human genome, 406 proteins with clear ion channel struc-
ture appeared. The characteristics of most of the cloned channels correspond well to the endog-
enous currents found in nerve, muscle, and other cells. The molecular constituents underlying other
endogenous currents is however still debated, and these channels appear to be composed by several
subunits from the same molecular family plus an additional number of accessory proteins. For
voltage-gated channels the pore-forming subunits are denoted
α
-subunits, whereas the accessory
subunits are called
β
,
γ
, or
δ
subunits.
13.1.5 I
ON
C
HANNELS
AND
D
ISEASE
The functional signii cance of specii c ion channels in the body can be difi cult to deduce from their
molecular function, but it can be studied in organs or whole animals using pharmacological tools or
selective toxins. Transgenic animals also provide valuable knowledge, but the most precise infor-
mation about their role in humans has come from patients with diseases caused by dysfunctional
ion channels. The diseases are typically caused by a point mutation in a single ion channel gene,
and the diseases are jointly called channelopathies. The most frequent and well-known disease is
cystic i brosis, arising from a point mutation in the Cl
−
channel CFTR. In Northern Europe, 5% of
the population is heterozygous for a mutation in the CFTR gene, and the prevalence of the disease
is 0.5‰. Several types of cardiac arrhythmia (long and short QT syndromes, Brugada syndrome,
and Andersen syndrome) are caused by mutations in cardiac K
+
, Na
+
, and Ca
2+
channels. Mutations
in neuronal and muscular ion channel subtypes cause epilepsy, ataxia, and myotonia. Luckily most
of these are rare, but their study has given invaluable information about the role of the ion channels
in health and disease.
13.1.6 P
HYSIOLOGICAL
AND
P
HARMACOLOGICAL
M
ODULATION
OF
I
ON
C
HANNELS
In addition to the main mechanisms for ion channel activation (voltage, ligands), the channels may
also in some cases be modulated by small organic molecules. The ligand-gated ion channels exhibit
an endogenous ligand-binding site, so compounds with similar functionalities can make potent
drugs. The voltage-gated channels are not expected to naturally exhibit high-afi nity binding sites,
but may possess such as in the case of the dihydropyridine-binding site on the Ca
2+
channel. Most
drugs act as positive or negative modulators of the channel gating, but some may also just plug the
pore as the local anesthetics blocking the neuronal Na
+
channels or the neuromuscular blockers acting
on the nicotinic channel in the neuromuscular junction.
13.1.7 D
RUG
S
CREENING
ON
I
ON
C
HANNELS
The center-stage role of ion channels in many physiological responses has been stressed by func-
tional studies in cells, organs, and animals, by the emerging channelopathies as well as by the
successful use of ion channel modulating drugs. Current drugs only target a dozen of the known
channel subtypes, while most of the other 400 types are currently all being investigated as potential
