——Disorders Associated with
G protein-Coupled Receptors
The human genome may encode as many as 2000
different GPCRs. Their importance in human
biology is reflected by the fact that more than
one-quarter of all prescription drugs act as
ligands that bind to this huge superfamily of
A number of inherited disorders have been
traced to defects in both GPCRs and
heterotrimeric G protein .
What is G protein?
What is GPCR?
Diseases associated with G
protein and GPCR.
Heterotrimeric G-proteins were
discovered and characterized by Martine
Rodbell and his colleagues at the National
Institutes in the early 1970s.These proteins
are referred to as G proteins because they
bind guanine nucleotides,either GDP or GTP
Alfred G. Gilman
University of Texas
Center at Dallas Dallas,
TX, USA born 1941
National Institute of
Triangle Park, NC,
Born 1925, died 1998
Two switch domains have
been identified, that
change position when GTP
substitutes for GDP on
The G-protein coupled
receptor (GPCR) family
signals across the
They consist of seven
that are connected by
loops. The N-terminal
extremity is always
located on the
extracellular side while
the C-terminus extends
into the cytoplasm.
1. Signal transduction by GPCR
When a hormone or neurotransmitter binds
to a GPCR, it induces a change in conformation
in the extracellular ligand-binding site. This
change in conformation is transferred across
the plasma membrane and causes a change in
the cytoplasmic loops of the receptor which, in
turn ,leads to an increase in the affinity of the
receptor for a G protein ,they forms a
receptor-G protein complex.
Then interaction with the receptor induces
a conformational change in the alpha
subunit ,causing the release of GDP, which is
followed by binding of GTP.
While in the activated state, a single
receptor can activate a number of G protein
molecules, providing a means of signal
GPCRs are activated by a wide variety of ligands, including
neurotransmitters, hormones, growth factors, odorant
molecules and light, and are encoded by the largest gene
family in most animal,and GPCR have many activating pathway.
2.cAMP signal transduction pathway
G-protein coupled receptors (GPCRs) are one of
the largest gene families of signaling proteins.
Residing in the plasma membrane with seven
transmembrane domains, GPCRs respond to
extracellular stimuli that include catecholamine
neurotransmitters, neuropeptides, larger protein
hormones, lipids, nucleotides and other biological
molecules. When a GPCR binds its extracellular
ligand, it interacts with a G-protein to transduce a
signal across the membrane into the cellular
G-proteins are a heterotrimeric complex
containing a Ga subunit with GTPase activity, as
well as b and g subunits. Ga can exist in an active
state and an inactive state.
Ga in the off state has GDP bound and does not
activate downstream signaling molecules. When a
GPCR is activated by ligand, it stimulates Ga
subunits to bind GTP instead of GDP and become
active, dissociating from the receptor and from
the b/g subunits to activate downstream signaling
factors like the enzyme adenylyl cyclase that
synthesizes cyclic-AMP (cAMP) from ATP. Ga
turns itself back off again with its intrinsic
GTPase activity, hydrolyzing GTP to GDP to
become inactive again.
Human Diseases Linked to the G Protein Pathway
Defective G Protein