Regulation of signal transduction

The hormonal stimulus can be blunted or shut off at
several levels of the signal transduction system. (1)
The stimulus can be diminished by decreasing the
number of receptors at the cell surface. This can be
achieved by decreased production of the receptors by
the protein-manufacturing mechanism of the cell.
Alternatively, the receptor proteins themselves are inactivated
or destroyed during the course of their function,
one example being endocytosis of the receptor
prior to intracellular destruction of the ligand. In any
event, this down-regulation of the receptor decreases
the responsiveness of the target tissue to the hormone.
(2) The Gs protein is inactivated by an intrinsic GTPase
activity that hydrolyses the bound GTP to GDP.
This GTPase activity allows the Gs protein to act as a
molecular switch: it rapidly turns the hormonal signal
on or off by binding or hydrolysing GTP, respectively.
(3) The inhibitory G protein, Gi, when activated by
other receptors, leads to direct inhibition of adenylyl
cyclase and thus cessation of cyclic AMP production.
(4) The ability to hydrolyse cyclic AMP by phosphodiesterase
allows the cell to respond transiently to a
given signal.
An additional mechanism of regulating signal
transduction, known as desensitization, allows a receptor
to be rapidly inactivated and then reactivated
despite the continued presence of a stimulus of constant
intensity. Persistent or excessive stimulation of
a G protein-coupled receptor leads to activation of a
G protein-coupled receptor kinase (GRK) that phosphorylates
the receptor. The receptor then binds an
arrestin protein which sterically prevents signalling to
the G protein (Lefkowitz, 1998). The family of GRKs
includes at least six members (GRKs 1–6) of which the
most thoroughly investigated are rhodopsin kinase
(GRK1) and β-adrenergic receptor kinase (GRK2).
GRKs recognize only the liganded or stimulus-modifi
ed forms of the receptors that they phosphorylate
(Lorenz et al., 1991). Desensitization of rhodopsin,
the photoreceptor in the rod cells of the retina, occurs
in less than one second following light stimulation,
thereby preventing a brief fl ash of light from being
perceived as continuous illumination.