and molecular modeling studies of these proteins. Early work suggested that there were
three types of heterotrimeric G protein: Gs,Gi, and Gt; where Gsand Gieffected stimu-
lation and inhibition of adenyl cyclase, respectively, and Gtcoupled rhodopsin to regu-
lation of photoreceptor cell function. Currently, approximately 40 heterotrimeric G
protein subunits have been identified, and for most of these G proteins multiple sub-
types show unique distributions in the brain and peripheral tissues. Analogous studies
have also shown that each αunit has two domains: the GTPase activity domain and the
GTP-binding site domain.
G proteins play a role in various diseases and in the long-term response to various
drugs. If the GTP is replaced by a nonhydrolyzable synthetic analog, guanyl-5'-yl-
imidodiphosphate (Gpp(NH)p; the anhydride oxygen is replaced by an NH group), the
reaction cannot be terminated, and cAMP will be produced continuously. The GTPase,
which normally terminates the active state, can also be inactivated by cholera toxin. The
potentially fatal diarrhea and electrolyte loss that occur in cholera reflect the fact that
cAMP is an activator of fluid secretion in the intestine. G proteins are also involved in
other diseases. Neurofibromatosis type 1, a familial disorder characterized by multiple
benign tumours of glial cells, is due to a genetic mutation that alters GTPase activity,
which in turn leads to abnormal cellular growth. In addition to such involvement in
specific disease states, G proteins are also involved in the body’s response to chronic
exposure to psychoactive drugs. Drug-induced alterations in G protein subunit concen-
trations influences signal transduction pathways in the brain, contributing to both the
addictive and therapeutic properties of these drugs.
An exciting development in G-protein-mediated signal transduction research has
been the realization that proteins produced by oncogenes (cancer-causing genes) are
also GTP-binding proteins.
2.10.2 The Guanylate Cyclase SystemThe second type of signal transduction utilizes cyclic GMP (cGMP) instead of cAMP
as second messenger. It plays a role not only in insect behavior but also in the human
retina and in the functioning of atrial natriuretic factor, a hormone produced by the heart
which regulates blood pressure. It is quite likely that cGMP can also act through Ca^2 +
as a third messenger in activating Ca-dependent protein kinases.
2.10.3 The Inositol Triphosphate–Diacylglycerol SystemThe third widely utilized signaling pathway is based on phosphatidylinositol,a normal
constituent of the cell membrane. The extracellular signal is received by a membrane-
bound receptor that interacts with a Gsprotein, activating phospholipase C (phos-
phatidylinositol diphosphate [PIP 2 ] phosphodiesterase), an enzyme that cleaves
phosphate diesters. The two products of this cleavage reaction are inositol triphosphate
(IP 2 ) and diacylglycerol (DG), both of which act as second messengers, but in different
cellular compartments. The structure of this G-protein receptor is similar to that of the
other G proteins (see figure 2.5); a comparison of this DG/IP 3 G protein to the previously
described adenylate cyclase system is shown in figure 2.6.
RECEPTORS: STRUCTURE AND PROPERTIES 95