interferons and cytokines. These molecules are either lipophilic or hydrophilic.
Lipophilic signalling molecules such as the steroid hormones (progesterone, oestrogen
and testosterone) and non-steroid hormones (thyroxine and triiodothyronine) can
readily cross the cell membrane, in which case they bind to receptors located in the
cytoplasm. These receptors have twobinding domains: an agonist-binding domain
and a DNA-binding domain. Binding of the lipophilic agonist to its site results in a
receptor–agonist complex that is able to pass through pores in the nuclear membrane
into the nucleus where it interacts with a specific DNA sequence, termed ahormone
response element, to regulate (activating or repressing) the transcription of down-
stream genes. For this reason, the receptors are referred to asnuclear receptors. In the
majority of cases of intercellular signalling, however, the signalling agonist is hydro-
philic and therefore incapable of diffusing across the cell membrane. The receptors for
such agonists are therefore embedded in, and span, the cell membrane with the
agonist-binding domain exposed on the extracellular side. This chapter will consider
the molecular nature and mode of action of such cell surface receptors.
Cell membrane receptor proteins possess three distinctdomains:- Extracellular domain: This protrudes from the external surface of the membrane and
contains all or part of the agonist-binding domain known as theorthosteric agonist-
binding site. - Transmembrane domain: This is inserted into the phospholipid bilayer of the
membrane and may consist of several regions that loop repeatedly back and forth
across the membrane. In some cases these loops form a channel for the ‘gating’ (hence
the channel may be open or closed) of ions across the membrane, whilst in other
receptors the loops create part of the orthosteric site. - Intracellular domain: This region of the protein has to respond to the extracellular
binding of the agonist to initiate the transduction process. In some cases it is the site of
the activation of enzyme activity within the receptor protein, commonly kinase
activity, or is the site that interacts with effector proteins.
The existence of three domains within receptor proteins reflects theiramphipathic
nature in that they contain regions of 19 to 24 amino acid residues possessing polar
groups that are hydrophilic, and similar sized regions that are rich in non-polar
groups that are hydrophobic and hence lipophilic. The hydrophobic regions, generally
in the form ofa-helixes, are the transmembrane regions that are inserted into the non-
polar, long-chain fatty acid portion of the phospholipid bilayer of the membrane.
Superfamilies of receptor proteins can be recognised from the precise number of
transmembrane regions each possesses. In contrast, the hydrophilic regions of the
receptor are exposed on the outside and inside of the membrane where they interact
with the aqueous, hydrophilic environment.17.1.2 Classification of cell membrane receptors
Studies of the structure of membrane receptors and of the mechanisms of their signal
transduction have led to the identification of three main classes of cell membrane
receptors:661 17.1 Receptors for cell signalling