Biomedical Engineering Reference
In-Depth Information
-subunits
are therefore of particular interest, since compounds capable of selectively blocking Na
v
1.7-Na
v
1.9
channels could have great potential as analgesics.
models of inl ammatory and neuropathic pain. From a therapeutic point of view, these
α
13.4.3 P
HARMACOLOGY
OF
V
OLTAGE
-G
ATED
S
ODIUM
C
HANNELS
A large number of natural products (peptides and alkaloids) have been found to bind Na
v
s with high
afi nity. Radioligand-binding, photoafi nity-labeling, and mutagenesis techniques have been used
to identify the regions of the
-subunit to which these substances bind. Six binding sites for these
toxins are therefore used to provide the conceptual framework for understanding the pharmacology
of Na
v
s (Table 13.3; Figure 13.9B). Given the high degree of homology between the Na
v
1-subunits,
very few examples of subunit-selective toxins are known. The substances mentioned in Table 13.3
thus bind to nearly all Na
v
1 subunits. Most toxins act as gating modii ers, and only tetrodotoxin and
saxitoxin binding to site 1 are pore blockers.
In addition to these different toxins, a number of clinically used drug molecules are known
to exert their pharmacological action through inhibition of Na
v
function. Consistent with the
physiological roles of Na
v
s, these drugs include antiepileptic compounds (carbamazepine, lam-
otrigine, and phenytoin), local anesthetic and analgetic compounds (lidocaine), and drugs used to
treat cardiac arrhythmia (class I antiarrhythmics including quinidine, lidocaine, mexiletine, and
l ecainide).
α
TABLE 13.3
Toxin-Binding Sites on Na
v
Channels
Site No.
Site Location
Toxins Binding to Site
Mechanism of Action
1
Selectivity i lter of pore
Tetrodotoxin, saxitoxin
Pore block
2
Interface between the S6
segments of domains I and IV
Plant alkaloid toxins:
grayanotoxin, batrachotoxin,
and veratridine
Inhibition of inactivation and
channel opening at resting
potential
3
Outer pore loop regions of
domains I and IV
Sea anemone peptide toxins
and
Slow inactivation
α
-scorpion toxins
4
Extracellular S3-S4 loop close
to the voltage sensor
Large β-scorpion peptide
Enhance opening at negative
membrane potential
5
Interface between the IS6 and
IVS5 segments
Plant alkaloids ciguatoxins
and brevetoxins
Enhance activation and
inhibit inactivation
6
Unknown
δ
-Conotoxins
Slow inactivation
13.5 CHLORIDE CHANNELS
Most cells have anion channels and the primary ion permeating these is Cl
−
. The ClC channel
family members are involved in transepithelial transport, acidii cation of synaptic vesicles, and
endocytotic trafi cking. The ClC proteins are unique and are widely expressed in intracellular
organelles and not in the plasma membrane. Surprisingly, some of the ClC proteins show char-
acteristics of ion transporters. The CFTR Cl
−
channel is an ABC protein involved in transepithelial
transport, and dysfunction of this Cl
−
channel causes cystic i brosis. The CFTR protein has
been extensively used in attempts to establish a gene therapy for cystic i brosis without success.
Ca
2+
-activated and volume-activated Cl
−
currents have been characterized in native cells, but
these have not been identii ed at a molecular level yet. The pharmacology of Cl
−
channels is cur-
rently quite poor.
