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(RGS). This group of over 20 proteins can be divided into five subfamilies based on

sequence homology. They all have two actions namely they reduce the binding of the

GaGTP to the effector and they act as GTPases accelerating the hydrolysis of GTP to

GDP by a factor of over 2000-fold, hence they are also referred to asGTP-accelerating

proteins(GAPs). As a consequence of this latter activity, RGSs effectively regulate the

duration of the response resulting from the activation of a GPCR.

Kinetics of the activation of and signalling by GPCRs

Spectroscopic techniques, especially FRET, have been used to evaluate details of the

kinetics and mechanisms of GPCR-mediated signals. Such studies have shown that

agonist binding, the activation of the receptor and interaction with the G-protein all

Desensitisation

Internalisation bg

PP

P

PP

Agonist stimulation

b-Arrestin-dependent

signalling

b-Arrestin-

dependent

ERK

b-Arrestin

1/2

Raf ERK

MEK

GRK

5/6

G-protein-

dependent

signalling

Second

messengers

E

Ga

Ga

b-Arrestin

1/2

GRK

2/3

AP2

Clathrin

Internalisation

Ga bg

Fig. 17.10Functional specialisation of the different GRKs. Upon agonist stimulation, GRK2 and GRK3

are recruited to the plasma membrane by interacting with Gbgsubunits. They have a predominant role in

receptor phosphorylation,b-arrestin recruitment, desensitisation and internalisation. GRK5 and GRK6 are

constitutively associated with the plasma membrane. They are both required forb-arrestin-dependent ERK

activation, although the locus of their action might be at the receptor or downstream. In some systems,

GRK5 and GRK6 can also mediate desensitisation and internalisation. E, second-messenger-generating

enzyme. (Reproduced from Reiter, E. and Lefkowitz, R. J. (2006). GRKs andb-arrestins: roles in receptor

silencing, trafficking and signalling.Trends in Endocrinology and Metabolism, 17 , 159–165, by permission

of Elsevier Science.)

697 17.4 Mechanisms of signal transduction