near the N-terminal end for the C-terminal region of the receptor and a guanine
nucleotide-binding site that also possess GTPase activity. Although theasubunit
contains the binding site for the receptor, binding only occurs when theasubunit
is bound to thebgdimer. Studies have revealed a very complex picture of the
G-proteins. Sixteen human genes and splice variants encodeasubunits giving rise
to at least 28 distinct types; five genes encodebsubunits and 14 genes thegsubunits.
The potential number of different Gabgfunctional trimers is therefore very large.G-protein subgroups
The most important are:- the Gssubgroup which stimulate adenylyl cyclase. It includes Golfcoupled to olfactory
receptors; - the Gisubgroup which inhibit adenylyl cyclase and activate some Ca^2 þand Kþ
channels; - the Gqsubgroup which couple receptors to calcium mobilisation through
phospholipase Cbthat in turn generates the two second messengers inositol
trisphosphate (IP 3 ) and diacylglycerol (DAG); - the Gosubgroup which reduce the probability of opening of some voltage-gated Ca^2 þ
channels involved in neurotransmitter release; - the Gtsubgroup which stimulate phosphodiesterase following light stimulation of the
retina involving transducin; and - the G12/13subgroup which is involved in the regulation of the cytoskeleton and
processes related to movement. The subgroup activates inducible nitric oxide
synthetase and the Naþ/Hþexchanger. The action involves the low-molecular-weight
protein Rho.
The G-proteinasubunit family is divided into four subgroups based on sequence
homology: GSa,Gi/oa,Gqaand G 12 / 13 a. Each subgroup has been further divided into
specific isotypes. The Gasubunit nomenclature is used to classify GPCRs, hence
GPCRs are referred to as GS-, Gi-orGq- etc. reflecting their primary signalling
pathway as discussed below. Since the number of human GPCRs is far greater than
the number of human G-proteins it is obvious that each member of the Gasubgroups
must be able to interact with many GPCRs.The G-protein cycle
Agonist binding to the GPCR triggers aG-protein cycle:- In the normal resting state, the trimeric G-protein has a molecule of GDP bound to the
asubunit. At this stage the G-protein is not coupled to the receptor but it is firmly
attached to the inner face of the cell membrane. - An agonist binds to its binding site on the GPCR and induces a rapid allosteric
conformational change that activates the G-protein binding site located in intracellular
loops, resulting in a GPCR–G-protein complex. The complex interacts by diffusion
translocation with a G-protein–adaptor complex that binds to theasubunit.
692 Cell membrane receptors and cell signalling