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3 Drug actionThe insulin receptor consists of twoαand twoβ-subunits, the latter span the cell
membrane. When a ligand binds to theα-subunits, intracellular tyrosine residues
on itsβ-subunits are phosphorylated, so activating their tyrosine kinase activity. The
activated enzyme catalyzes phosphorylation of other protein targets, which generate
the many effects of insulin. These effects include the intracellular metabolic effects,
the insertion of glucose transport protein into the cell membrane as well as those
actions involving gene transcription.3) Regulation of gene transcription
Steroids and thyroid hormones act through intracellular receptors to alter the expres-
sion of DNA and RNA. They indirectly alter the production of cellular proteins so
their effects are necessarily slow. These cytoplasmic receptors act as ligand-regulated
transcription factors; they are normally held in an inactive form by association with
inhibitory proteins. The binding of an appropriate hormone induces a conforma-
tional change that activates the receptor and permits translation to the nucleolus,
which leads to association with specific DNA promotor sequences and production
of mRNA.Adrenosteroid hormones
There are two types of corticosteroid receptor: the mineralocorticoid receptor, MR,
and the glucocorticoid receptor, GR. The GR receptor is wide spread in cells, includ-
ing the liver where corticosteroids alter the hepatic production of proteins during
stress to favour the so-called acute-phase reaction proteins. The MR is restricted
to epithelial tissue such as renal collecting tubules and colon, although these cells
also contain GR receptors. Selective MR receptor activation occurs due to the pres-
ence of 11-beta hydroxysteroid dehydrogenase, which converts cortisol to cortisone:
cortisone is inactive at the GR receptor.Other nuclear receptors
The new antidiabetic drug rosiglitazone is an agonist at a nuclear receptor, perox-
isome proliferator-activated receptor, which controls protein transcription associ-
ated with increased sensitivity to insulin in adipose tissue.Dynamics of drug–receptor binding
The binding of a ligand (L) to its receptor (R) is represented by the equation:
L+R↔LR.
This reaction is reversible. The law of mass action states that the rate of a reaction
is proportional to the concentrations of the reacting components. Thus, the velocity
of the forward reaction is given by:
V 1 =k 1 ·[L]·[R],