connexons(one in each of the two adjoining cells); each connexon is composed of six
homologous subunits, the connexin proteins. Each connexin protein traverses the mem-
brane four times (via segments M1–M4); the portion of the protein between M2 and M3
forms an intracytoplasmic “hinge region” which characterizes the connexins in either α
orβfamilies; the M3 transmembrane segment is amphipathic and lines the lumen of the
channel pore; the C1 (between M1 and M2) and C2 (between M3 and M4) extracellular
loops contain three cysteine residues; the amino and carboxy termini are both intracyto-
plasmic. Connexin proteins are encoded by a single gene family; in humans, these genes
map to at least four chromosomes, including chromosome X. Gap junctions form elec-
trotonic synapses between neurons that carry electrical current from cell to cell predom-
inantly through the transport of K+ions. Experimentally, gap channels may be blocked
with lipophilic agents such as heptanol, octanol, glycyrhetinic acid, or oleic acid; no gap
junction active agent is currently in human clinical use, although this is an active area of
ongoing research. Therapeutically, gap channel agents could be used to treat neurologi-
cal disorders such as epilepsy or migraine. Also, since gap junctions mediate intercellu-
lar communication that influences cellular growth rate, gap junction agents may provide
a novel therapeutic strategy to the treatment of tumorigenesis.
G-coupled proteins transduce a message from the external environment to the inte-
rior of the cell through a series of coupled molecular events. These have been described
in chapter 2.
Another transport structure, used for the passage of large molecules such as
hormone–receptor complexes, is the coated pit. The coat is formed by a network of
clathrinmolecules in a regular pattern. After binding of the ligand—and, frequently,
clustering of ligand–receptor complexes—the coated pit deepens, invaginates, and
undergoes endocytosis, to become a coated vesicle. The clathrin coat is shed and the
vesicle fuses with a preformed endosome, which releases the enclosed molecules, often
to a lysosome. The receptors, still embedded in the internalized membrane, can then be
recycled to the plasma membrane via vesicles pinched off the endosome. Alternately,
internalized ligand–receptor complexes can be transported intact to the other end of the
cell and the ligand released by exocytosis.
There are also a number of specialized proteins involved in functions unique to given
cellular populations. Cells that have to withstand severe deformation—such as red
blood cells, which must squeeze through narrow capillaries—contain a scaffold directly
below the plasma membrane. Large glycoprotein molecules hold small ankyrin mole-
cules on the inside. Long filaments of spectrinconnect the ankyrins, and short actin
chains secure the crossover points of spectrin molecules like braces. This subsurface
mesh reinforces the delicate plasma membrane, providing the toughness and flexibility
required during the long life of erythrocytes. The mesh can also anchor enzymes such
as protein kinases.
7.4 TARGETING CELL MEMBRANE STRUCTURES:
VOLTAGE-GATED ION CHANNELS
7.4.1 Channel StructureThe elucidation of the amino acid sequence of many channels now allows structural and
phylogenetic comparisons. The nicotinic acetylcholine receptor (AchR) Na+-channel,
ENDOGENOUS CELLULAR STRUCTURES 413