the dissociation of the Gasubunit from the Gbgsubunit allowing the Gasubunit
to initiate signalling, for example by activating adenylyl cyclase, or the agonist-
bound RTK may directly associate with a GPCR through scaffold molecules such as
RGS, allowing the RTK to use components of GPCR signalling such as GRK/b-arrestin.
A good example is the regulation of glucose metabolism involving theb-adrenergic
receptor (a GPCR) and its regulation by the insulin receptor. The ability of the insulin
receptor to counter the release of glucose by the action of catecholamines on the
adrenergic receptor leads to the tight control of serum glucose levels. This control by
the insulin receptor of theb-adrenergic receptor appears to operate by two (at least)
mechanisms, one involving the internalisation of theb-adrenergic receptors via GRK/
b-arrestin hence decreasing the sensitivity of the cell to circulating catecholamine, the
other at the level of the activation of RGSs hence terminating the action of the
activatedb-adrenergic receptor. Crosstalk between the two GPCRsm-opioid receptor
(MOR) anda2A-adrenergic receptor (a2AAR) has been shown to proceed via a direct
conformational change-induced inactivation of the noradrenaline-occupieda2AAR
by the binding of morphine to the MOR. The two receptors form a heterodimer and
activate common transduction pathways mediated through the inhibition of Giand Go.
The inhibition of thea2AAR occurs within a subsecond of the morphine binding and
terminates a downstream MAP kinase cascade induced by thea2AAR.
Nodes characteristically consist of a group of related proteins that are essential
for the receptor-mediated signal but such that two or more of these proteins have
unique roles within the network and are therefore the source of divergence within the
network (Fig. 17.12). Many networks contain cascades of cycles formed by two or
more interconvertable forms of a signalling protein. This protein is modified by two
opposing enzymes, commonly a kinase and a phosphatase for phosphoproteins or a
guanosine nucleotide exchange factor (GEF) and a GTPase-activating protein (GAP) for
G-proteins. Such cascades afford the property ofultrasensitivityto the input signal
particularly under conditions in which the enzymes are operating near saturation.17.5 Receptor trafficking
17.5.1 Membrane structure
Detailed studies of cell membranes and of the area of the membrane occupied by
signalling receptors have revealed that the membrane is very patchy with segregated
regions ormicrodomainsof different protein and lipid structure. One such type of
these microdomains arelipid raftsthat are dynamic structures rich in sphingolipids,
glycosphingolipids, sphingomyelin and cholesterol and as a result are less fluid than
the remainder of the membrane. Lipid rafts are involved in the organisation of
receptors and their associated signal-transduction pathways. A subset of lipid rafts
arecaveolaecharacterised by their invaginated morphology produced as a result of
cross-linking between a constituent protein calledcaveolin. There is evidence that a
given receptor accumulates in either lipid rafts or caveolae but not both.703 17.5 Receptor trafficking