9780521516358book.pdf

to be distributed in specific regions of the brain. In the resting state the channels are

closed, but the binding of glutamate leads to the production of a second messenger

that triggers the opening of the channel and the movement of ions. The channel then

becomes desensitised and closes as the glutamate begins to dissociate returning the

receptor to its resting state. The receptors are targets for a number of drugs such as the

benzodiazepines. mGluRs contain an allosteric site that is a potential target for drugs

involved in the treatment of Parkinson’s disease (mGluR4), schizophrenia (mGluR5)

and addiction (mGluR2).

• Frizzled/Taste family: These two subgroups of the same family have 11 and 25
  members respectively. The Frizzled receptors are named after theDrosophilatissue
  polarity gene known asfrizzled. The receptors bind Wnt glycoproteins involved in
  transduction pathways for the control of gene expression in embryonic development
  and regulation.

G-protein structure

G-proteins are heterotrimeric, consisting of one of each of three subunits,a(40–45 kDa),

b(36–40 kDa) andg(8 kDa), which are loosely attached to the inner surface of the

cellular membrane through lipophilic tails on theaandgsubunits. Thebandg

subunits are firmly attached to each other but the linkage to theasubunit is weaker.

In addition to the binding site for thebsubunit, theasubunit has a binding site

D

Gs

P

PDZ

Arr GRKRAMPs SH2

SH3

Gi

Fig. 17.7Schematic diagram of a hypothetical G-protein-coupled receptor. Labels denote general regions of

interaction of the receptor with other cellular proteins including different G-proteins (Giand Gs), PDZ, SH2 and

SH3-domain proteins, receptor-activity-modifying proteins (RAMPs), arrestin (Arr), G-protein-coupled receptor

kinase (GRK), sites for dimerisation with other GPCRs (D), and phosphorylation sites that lead to uncoupling

and internalisation (P). Any one of these active processes could be considered a form of expression of efficacy.

The figure is a general description of various loci for protein interactions, but does not represent accurate

locations, as, in most cases, these are not well characterised. (Reproduced from Kenakin, T. (2002). Efficacy

at G-protein-coupled receptors.Nature Reviews Drug Discovery, 1 , 103–110, by permission of Nature

Publishing Group.)

691 17.4 Mechanisms of signal transduction