- Binding of the GPCR–G-protein complex to the G-protein–adaptor complex induces
an allosteric conformational change in the guanine nucleotide-binding site on thea
subunit of the G-protein causing the site to be more accessible to the cytosol where
[GTP]>[GDP] resulting in the dissociation of the GDP and the formation of a
transient ‘empty state’. - GTP binding to the nucleotide-binding site on theasubunit triggers a second, rapid
conformational change in theasubunit causing the dissociation of GTPasubunit and
leaving the Gbgsubunits as a dimer. Both the GTPasubunit and the Gbgdimer remain
attached to the cell membrane. - GTPasubunit and/or the Gbgdimer bind to an inactive effector molecule causing its
activation or inhibition. Examples of such effector molecules include adenylyl
cyclase, phospholipase C, cyclic nucleotide phosphodiesterases and a number of ion
channels. - Hydrolysis of GTP to GDP by the GTPase site of theasubunit, with the involvement of
RGS proteins (see below for further details), terminates the activation or inhibition by
reversing the conformational change originally induced by the receptor–agonist
complex. This facilitates the dissociation of theasubunit from the effector and its
reassociation with the Gbgdimer, thus completing the cycle. Concomitantly, the
binding of the receptor–agonist complex to the G-protein reduces the affinity of the
receptor for its agonist encouraging its dissociation from its binding site resulting in
the reformation of the inactive conformation of the receptor and hence terminating its
binding to the G-protein.
Two important examples of the role of Ga-GTP as a transducer are the activation of
the key enzymes adenylyl cyclase, that converts ATP to the second messenger
cAMP, and phosphodiesterase (phospholipase C) that cleaves phosphatidylinositol-4,
5-bisphosphate (PIP 2 ), a component of the cytoplasmic side of the cell membrane, to
two second messengers – inositol-1,4,5-trisphosphate and diacylglycerol. Most
examples of the transducer role of the Gbgdimer are linked to the activation of Gi
and Go. Examples include the activation ofb-adrenergic receptor kinase (bARK),
phospholipase A 2 and the Kþchannel GIRK (G-protein-activatedinwardlyrectifying
potassium channel).
A given G-protein may be activated by a large number of different receptors
(referred to asG-protein promiscuity), whilst a given receptor may interact with
different G-proteins and/or produce more than one response (referred to asreceptor
promiscuity). A receptor capable of activating more than one type of G-protein and
hence of initiating more than one response is referred to as apleiotropic receptor
(meaning it has multiple phenotypic expressions). An example is the human adeno-
sine receptor that can couple to Gi,Gsand Gq. Some GPCRs are capable of binding
several agonists each of which can induce a specific conformational change that
preferentially selects a specific G-protein that in turn leads it to activate a specific
transduction pathway. Examples are the 5-HT receptors, 13 of which have been
identified to date and 12 shown to be GPCRs (Table 17.1). Such multiple roles for a
given agonist have lead to the concepts offunctional selectivity(Fig. 17.8) andbiased
agonism(Fig. 17.9).693 17.4 Mechanisms of signal transduction