Page 260 - The Toxicology of Fishes

240 The Toxicology of Fishes

Ligand
+
Receptor I
AFFINITY
K D
Ligand–Receptor I
INTRINSIC
EFFICACY
Ligand–Receptor A EFFICACY
TISSUE K E
COUPLING
RESPONSE
I
FIGURE 5.2 The pathway to receptor-mediated response. The ligand interacts with an inactive receptor (Receptor ) to form
a stable complex. The strength of this interaction is termed affinity and is typically represented by the equilibrium dissociation
A
constant (K D ). The ability of the ligand to then convert the receptor to an active form (Receptor ) is termed intrinsic efficacy.
The magnitude of the response produced by the active receptor also depends on concentrations of other factors in the
particular cell type, collectively termed tissue coupling. Intrinsic efficacy and tissue coupling together form the efficacy of
the ligand–receptor complex, which is represented by the constant K E in the operational model of receptor action.

differ in their ability to activate the receptor. The ligand–receptor interaction, therefore, may be thought
of as a two-step process leading to activation (Figure 5.2): (1) the interaction of the ligand and the
receptor (governed by a property termed affinity), and (2) the conversion of the receptor to an active
form (a property termed efficacy).

Affinity
Ligand “binding” by a receptor is typically the result of several noncovalent interactions. The strength
of this binding is termed affinity. The interaction of receptor and ligand is reversible, with rate constants
for the association and dissociation of the ligand with the receptor:

LR → LR (5.1)
+
k 1

←
k 2
where L, R, and LR are the ligand, receptor, and ligand–receptor complex, respectively, and k and k 2
1
are the association and dissociation rate constants. Typically association (or “on”) rates are several orders
of magnitude greater than dissociation (or “off”) rates. At equilibrium, association and dissociation occur
at an equal rate. If a single equilibrium dissociation constant (K ) is defined to replace the rate constants:
D
K D = k 2 (5.2)
k 1
then we can derive the following expression relating ligand concentration and the fraction of receptor
that is occupied by ligand:
[LR ] = [ ]
L
[ R T] [] K D (5.3)
L +
where R is the total amount of receptor in the cell. This relationship is a variation of the Langmuir
T
binding isotherm (Langmuir, 1916).
From Equation 5.3, it is evident that K is equivalent to the ligand concentration at which half the
D
receptor is in a complex with ligand. At lower values of K , less ligand is needed to occupy the receptor,
D
indicating a stronger affinity of the receptor for the ligand. Because on rates are much faster than off
rates, the value for K is typically in the micromolar to picomolar range.
D