The potassium channel, on the other hand, is blocked by both tetraethylammonium
salts (7.3, TEA) and nonyl-triethylammonium (7.4)salts, indicating the presence of a
hydrophobic binding site that accommodates the nonyl group. Both blocking agents must
be applied intra-axonally, which is understandable if one considers that the K+current
is always directed outward.
7.4.1.2 Characterization of the Voltage-Gated Ion Channels
MacKinnon, who was awarded the 2003 Nobel Prize in Chemistry, has recently pro-
vided the first in-depth experimental structure of an ion-selective channel. He studied a
transmembrane K+channel composed of four identical subunits clustered symmetrically
around a central pore. Each subunit contributes two membrane-traversing α-helices,
which are connected by a peptide loop, called the P-region, that constitutes the selec-
tivity filter of the channel. These two α-helices are tilted away from the central axis
towards the extracellular side of the channel. Four inner α-helices from each of the sub-
units line the pore toward the cytoplasmic end. The inner and outer mouths of the pore
are lined with amino acid side chains. The selectivity filter is lined by three main-chain
carbonyl groups from the protein backbone of each of the four subunits. The channel is
occupied by three K+atoms.
MacKinnon’s landmark studies have gone a long way to providing a rigorous under-
standing of the K+channel. These results can be extrapolated to a more fundamental
understanding of both the Na+and Ca^2 +channels.
7.4.2 Targeting the Sodium Channel Protein: Local AnestheticsLocal anestheticsare molecules that are capable of reversibly blocking impulse con-
duction along nerve fibres (and other excitable membranes) that exploit the sequential
opening of sodium channels as the primary biochemical process for the transmission of
electrical information; by means of this action, these molecules can inhibit perception
of pain sensation from specific regions of the body. Blocking Na+channels is an ideal
method for achieving local anesthesia. The pain-producing stimulus is still present, but
the nerves that carry the pain-conveying information to the brain have been blocked;
thus, the brain never receives the information, which renders it incapable of perceiving
the pain. Local anesthetics must be differentiated from general anesthetics. Local anes-
thetics block perception of pain from a discrete body region while leaving the individ-
ual conscious; they function by blocking voltage-gated ion channels, such as the Na+
channel, within the peripheral nervous system (i.e., the peripheral spinal nerves).
General anesthetics block perception of pain within the entire body by inducing a state
of unconsciousness; they function by blocking ligand-gated ion channels, such as the
ENDOGENOUS CELLULAR STRUCTURES 415