R or T state), signaling subsequent links in the receptor–effector chain that ultimately
trigger the biological effect. Besides initiating the effector step of the drug action, effec-
tors are often amplifiers, magnifying an inconspicuous initial event like the binding of
a few thousand ligand molecules at 10–9–10–10M concentration. Amplification can take
the form of a cascade,as in the well-known case of epinephrine or glucagon: these hor-
mones initiate glycogenolysis through a series of enzyme activation steps, causing the
initial effect to be magnified approximately 100 million fold. Indeed, one is struck by
the omnipresence of the enzyme adenylate cyclase (AC), which serves as first amplifier
or effector in a large number of drug-initiated cascades as well as in numerous bio-
chemical chains of events in enzymology. The cAMP that is subsequently produced
activates kinases, which phosphorylate different proteins acting as final effectors. Since
the majority of receptors are localized in cell membranes, this sequence of events con-
stitutesintercellular communication.
Another type of effector is the ion channel of an excitable membrane, which in its
R (open) conformation allows the passage of about 10,000–20,000 ions in a single
impulse, resulting in either membrane depolarization or polarization and a multitude of
possible physiological phenomena.
2.7.2.3 The Mobile Receptor Model
The mobile receptor model was proposed by Cuatrecasas and by De Haën in an attempt
to explain why so many different drugs, hormones, and neurotransmitters can activate
adenylate cyclase. According to classical concepts, a recognition site is permanently
associated with an effector site, and will regulate its operation on a one-to-one or some
other stoichiometric basis. The recognition site is, of course, specific.
If this hypothesis is applied to the case of adenylate cyclase, one of two conditions would
have to be assumed: that there are either as many adenylate cyclase isozymes as there are
receptors acting through them, or that adenylate cyclase would need an enormous variety
of specific recognition sites that can answer to many ligands. The latter possibility would
imply a lack of selectivity. However, there is no evidence for either assumption.
The mobile receptor concept is an attempt to offer a solution to this problem, in rec-
ognizing that the lipid membrane is a two-dimensional liquid in which the embedded
proteins can undergo rapid lateral movement or translation at a rate of 5–10 μm/min—
an enormous distance on a molecular scale. The recognition protomer of a receptor com-
plex therefore need not be permanently associated with an effector molecule, and thus
no stoichiometric relationship is required. Instead, the recognition protomer can undergo
rapid lateral movement and, when activated to the R state, can engage in what has been
dubbed a “collision coupling.” The R state of the receptor has the appropriate confor-
mation to trigger effector activity, which could be the opening of an ionophore or the
activation of adenylate cyclase. Therefore, different recognition sites can activate the same
adenylate cyclase molecule at different times through the same mechanism. By the same
token, a single recognition site could activate several adenylate cyclase molecules or other
effector systems during its active lifetime. Such multiple collision couplings can be seen
as the molecular explanation of positive cooperativity and the concept of receptor reserve.
There is no need to invoke multiple recognition sites on the enzyme or a multitude of
isoenzymes, only the physical separation of recognition and effector sites and their
RECEPTORS: STRUCTURE AND PROPERTIES 89