receptor structure and desensitisation. Mutagenesis studies of these serine residues
have shown that their replacement by non-polar amino acids minimises the suscepti-
bility of the receptor to acetylcholine-induced desensitisation. In contrast, replace-
ment of the serines by glutamates, which contain negatively charged carboxyl groups,
permanently desensitises the receptor. This phosphorylation-induced modulation of
receptor function is found in many other types of ion-transport proteins indicating a
common mechanism, but it is not clear whether or not phosphorylation is an essential
prerequisite for receptor desensitisation.17.4.3 Signal transduction through G-protein-coupled receptors (GPCRs)
The fact that over 800 human G-protein-coupled receptors have been identified and
verified emphasises their cellular importance. They are the largest group of signalling
transduction receptors and are responsible for a wide range of physiological processes
ranging from the transmission of light and odorant signals to hormonal action and
neurotransmission. Dysregulation of GPCRs is associated with several clinical condi-
tions such that many currently used drugs target these receptors (Section 18.2).
Although these receptors share a common 7TM structure (Fig. 17.7), their agonist-
binding (orthosteric) domains vary considerably. For small agonists (e.g. adrenaline,
histamine, dopamine, serotonin) the domain is partially embedded within a trans-
membrane helical structure but for large agonists, including the neuropeptides and
chemokines, the domain may span the extracellular loops or be located near the
N-terminal region.
Based on phylogenetic criteria, GPCRs have been classified into five families:- Rhodopsin family: This is the largest and most widely studied family. It currently
contains 672 verified members which are highly heterogeneous and have therefore
been divided into four subgroups,a,b,gandd. Theasubgroup contains many
receptors that are involved in basic physiological functions and hence are targets for
drug therapy. Examples include the H 1 and H 2 histamine receptors, the serotonin
receptors 5-HT1A, 5-HT1Dand 5-HT2A, the adrenergic receptors 1A, 2A, B1 and B2 and
muscarinic receptors. - Secretin family: This family is characterised by a long N-terminal tail containing six
cysteine residues linked by disulphide bridges and involved in ligand binding. The
family has 15 members which include the glucagon, calcitonin and secretin receptors.
They all activate adenylyl cyclase and couple through the same Gsprotein. Their
overexpression is commonly linked to human tumours. - Adhesion family: This family contains 33 members all of which bind cell adhesion
molecules such as integrins, cadherins and selectins, which are involved in the control
of mitogenesis, differentiation and the immune system. - Glutamate family: This family has 22 members all of which bind either glutamate
or GABA. They are involved in neurotransmission in the brain by controlling the
movement of ions such as Ca^2 þ,Naþand Clthrough ion channels. Their action
may be either excitatory or inhibitory. Members include the so-called metabotropic
glutamate receptors (mGluR) of which eight have been identified and each shown
690 Cell membrane receptors and cell signalling