9780521516358book.pdf

other ‘closed’, and that the role of glutamate is to stabilise the closed, active form.

In contrast, the GABABreceptor is a heterodimer involving two receptors from family

B. The explanation for the importance of this dimerisation of GPCRs is a topic of

current research but a number of points have emerged so far:

• Firstly, it appears to occur early in the biosynthetic pathway of the receptors,
  specifically in the endoplasmic reticulum, and is essential for the trafficking of the
  receptors into the membrane.


• Secondly, molecular modelling studies with the rhodopsin receptor have
  demonstrated that it can only effectively interact with subunits of a G-protein if it is a
  homodimer emphasising the importance of molecular size and conformation in
  receptor activity.


• Thirdly, the formation of heterodimers facilitates the opportunity for crosstalk
  between the two protomers. Such crosstalk has been demonstrated for a number of
  receptors including histamine H 1 receptors and GABABreceptors and there is growing
  evidence of the general importance of such receptor crosstalk in maintaining
  specificity from signal to cellular response.

(a) I

R

AB

Ligand I leads to Gicoupling

Coupling to Gi–leads to

effector response A

b b

ai aq

g g

(b)

R

AB

Ligand II leads to Gq coupling

Coupling to Gq–leads to

effector response B

II

b b

ai aq

g g

Fig. 17.9Functional selectivity. GPCRs often couple to multiple G-proteins. Functional selectivity is seen

when ligand binding influences which G-protein associates with the receptor by promoting distinct coupling

efficiencies. For example, binding of a distinct ligand (I) leads to activation of Giand effector responses initiated

through this G protein (a), whereas binding of a different ligand (II) to the same GPCR leads to activation of Gq

and to an alternative set of effector responses driven through this G-protein (b). (Reproduced from Gilchrist, A.

(2007). Modulating G-protein-coupled receptors: from traditional pharmacology to allosterics.Trends in

Pharmacological Sciences, 28 , 431–437, by permission of Elsevier Science.)

695 17.4 Mechanisms of signal transduction