7.6 TARGETING CELL MEMBRANE PROTEINS:
TRANSMEMBRANE TRANSPORTER
PROTEINS
The voltage-gated and ligand-gated ion channels enable the transmission of information
from cell to cell and along any given cell through the selective permeation of cellular
membranes to particular ions. Transport proteins, on the other hand, tend to subserve a
support or maintenance function by restoring chemical balance and metabolism within
a cell. The transporter proteins are membrane proteins that carry either ions or mole-
cules across membranes, typically in an energy-dependent fashion, usually using ATP
as the source of energy. These are “workhorse proteins” that function to restore and
maintain cellular metabolism and chemistry.
One of the most important families of transport proteins is the energy-consuming
pump family. These proteins literally pump ions across cellular membranes, requiring
energy to do so. In electrically excitable tissues, such as neural or cardiac tissue, the
electrical signal is transmitted in the form of the “action potential,” which involves
the sequential opening of voltage-gated ion channels along the course of the cellular
membrane. However, once the action potential has passed, it is the function of the Na/K
ATPase (“sodium pump”) protein to pump the ions back to where they belong so that
the cell is once again responsive to another action potential. Pump proteins, such as the
Na/K ATPase protein, are targets of drug design, as discussed in detail in section 7.6.1.
The other major class of transporter protein is the carrier protein. A prototypic
example of a carrier protein is the large neutral amino acid transporter. An important
function of the LNAA transporter is to transport molecules across the blood–brain
barrier. As discussed previously, most compounds cross the BBB by passive diffusion.
However, the brain requires certain compounds that are incapable of freely diffusing
across the BBB; phenylalanine and glucose are two major examples of such com-
pounds. The LNAA serves to carry phenylalanine across the BBB and into the central
nervous system. Carrier proteins, such as the LNAA transporter, can be exploited in
drug design. For example, highly polar molecules will not diffuse across the BBB.
However, if the pharmacophore of this polar molecule is covalently bonded to another
molecule which is a substrate for the LNAA, then it is possible that the pharmacophore
will be delivered across the BBB by “hitching a ride” on the transported molecule.
Another carrier-type protein is the Na+/glucose cotransporter protein. This carrier
must be “loaded” with both Na+and glucose in order to fulfil its function, which
involves the absorption of both Na+and glucose from the bowel. Knowledge of the mol-
ecular machinery of this protein has been instrumental in developing a simple but life-
saving therapy for the treatment of cholera. There is no specific antibiotic treatment for
cholera, since it is due to an exotoxin produced by the bacterium Vibrio cholerae. In
cholera, the mechanism of death involves severe dehydration (up to 20 L per day via
the bowel). The World Health Organization (WHO) promotes the use of an oral rehy-
dration solution consisting of NaCl (3.5 g), NaHCO 3 (2.5 g), KCl (1.5 g), and glucose
(20 g) per litre of water. By the simple measure of incorporating glucose into the rehy-
dration solution, thereby enabling water and Na+to be cotransported across the bowel
wall, the potentially lethal dehydration is successfully corrected although the frequent
discharge of stool is not prevented.
ENDOGENOUS CELLULAR STRUCTURES 433