Postjunctional Receptors
The similarity of the acetylcholine receptors among many species
and the abundance of acetylcholine receptors from the Torpedo
electric fish have greatly facilitated research in this area. The availability of
the messenger ribonucleic acids (mRNAs) of humans and other species and of deoxyribonucleic
acids (DNAs) has allowed the study of the receptor in artificial systems such as
oocytes from frogs and mammalian cells that do not express the receptor, such as
COS or fibroblast cells. It is also possible by molecular techniques to mutate receptors
to simulate pathologic states and then study receptor function in these artificial
systems. By using these and related techniques, much has been learned about the
synthesis, composition, and biologic function and the mechanisms that underlie physiologic
and pharmacologic responses in the acetylcholine receptors.[1]
[7]
[39]
[40]
[41]
It is evident that two isoforms of postjunctional
receptors exist, a junctional or mature and an extrajunctional or immature receptor
(see "Biology of Prejunctional and Postjunctional Nicotinic Receptors").[1]
[25]
The differences between receptor subtypes,
however, can be neglected in a general discussion of the role of receptors in neuromuscular
transmission.
The acetylcholine receptors are synthesized in muscle cells and
are anchored to the end-plate membrane by a special 43-kd protein known as rapsyn.
This cytoplasmic protein is associated with acetylcholine receptor in a 1:1 ratio.
[8]
The receptors, formed of five subunit proteins,
are arranged like the staves of a barrel into a cylindrical receptor with a central
pore for ion channeling. The key features are sketched in Figure
22-4
. The receptor protein has a molecular mass of about 250,000 daltons.
Each receptor has five subunits, which are designated α, β, δ, and
epsilon or γ; there are two subunits of α and one of each of the others.
[1]
[2]
Each of
the subunits consists of approximately 400 to 500 amino acids. The receptor protein
complex passes entirely through the membrane and protrudes beyond the extracellular
surface of the membrane and into the cytoplasm. The binding site for acetylcholine
is on each of the α-subunits, and these are the sites of competition between
the receptor agonists and antagonists. Agonists and antagonists are attracted to
the binding site, and either may occupy the site, which is located near cysteine
residues (unique to the α-chain) at amino acid positions 192–193 of the
α-subunit.[42]
Radiolabeled α-bungarotoxin
from the cobra, used to quantitate the receptor, binds to heptapeptide region 189–199
of the α-subunit.[43]
