From the Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892
The number of known forms of G protein The minireviews in this series address only three specific aspects of
the very broad and diverse range of "signaling by heterotrimeric G
proteins," aspects in which recent progress has been notable. An
attempt has been made to emphasize commonalities of the processes and pathways that are considered. Of necessity, however, experiments are done with specific G In 1957, when Sutherland and Rall (3, 4) described the basic properties
of an enzyme now known as adenylyl cyclase, its activation by
epinephrine, glucagon, and NaF, and the identification of its product
cAMP, G proteins and hormone receptors were unknown. Ten years later
the hormone-sensitive adenylyl cyclase was still viewed as a protein
complex in which activity of a catalytic unit was regulated in an
allosteric fashion by the interaction of a hormone ligand with a
specific site on a regulatory subunit. By the end of the 1960s,
however, Birnbaumer and Rodbell (5) had concluded from studies of fat
cell adenylyl cyclase, which is activated by multiple hormones, that
hormone receptors are distinct from the catalyst. A few years later
Orly and Schramm (6) directly demonstrated the independence of receptor
and cyclase, and in 1981, Shorr et al. (7) reported
purification of a Shortly after they deduced the separateness of receptors and cyclase,
Rodbell and Birnbaumer (8) detected a previously unsuspected role for
GTP in hormonal activation of the enzyme and described effects of the
nucleotide on hormone binding. Pfeuffer and Helmreich (9) separated a
GTP-binding protein from the adenylyl cyclase complex, and by 1977 Ross
and Gilman (10) reported that a 40-kDa GTP-binding protein could be
added back to an insensitive cyclase to restore activation by GTP, as
well as by NaF. This protein is now known as G During the late 1970s Cassel and Selinger (12) described a GTPase
activity that was stimulated by epinephrine in parallel with adenylyl
cyclase activity and was inhibited by cholera toxin, which was known to
activate the cyclase. They postulated that the hormone-activated
receptor interacted with Gs to facilitate release of bound
GDP and subsequent GTP binding. Hydrolysis of bound GTP to GDP then
inactivated Gs and completed the cycle. This is the
hormone-stimulated GTPase activity that is inhibited by cholera
toxin-catalyzed ADP-ribosylation of G While the adenylyl cyclase-G protein system was being unraveled, other
investigators were defining the light-activated cGMP phosphodiesterase
in retinal rod outer segments, which is associated with a
light-activated GTPase (transducin), and the photon receptor rhodopsin.
Numerous structural and mechanistic similarities between the two
systems became increasingly evident. By 1986, cDNA cloning provided
deduced amino acid sequences for G GTP hydrolysis is a very critical step in G protein signaling because
it is a "turn off" switch. The intrinsic rates of GTP hydrolysis by
G proteins differ widely. Casey and Gilman (14) wrote in a 1988 minireview that "More information is needed on interactions that may
influence the rate of the GTPase reaction that is catalyzed by an
During the 1980s and 1990s, mechanisms of signaling from what had
become a very large number of known G proteins, involving Forty years ago, the marvelous complexity of biological regulatory
reactions and molecules that would be revealed by the discovery of cAMP
and adenylyl cyclase could not have been imagined. Thus far, Nobel
Prizes for that and directly related discoveries have been awarded to
Sutherland (1971), Fischer and Krebs (1992), whose extensive studies of
reversible protein phosphorylation began with
cAMP-dependent protein kinase, and Gilman and Rodbell
(1994) for their work on heterotrimeric G proteins. There may well be more because these components are fundamental to critical signaling processes in essentially all eukaryotic cells, and much remains to be
learned.
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,
,
and
subunits, as well as the enormous number of receptors with
which they interact, and their diverse effectors, which influence
virtually all kinds of cellular processes, make this an obviously
important (and complicated) field. Fortunately, however, there are many
similarities among the structures and functional interactions of the G
protein subunits and the G protein-coupled receptors. This has
facilitated progress because it is often possible to apply information
obtained with one G protein and/or receptor to the characterization of
another system. At the same time, there is, of course, specificity in each of the protein-protein interactions that must in the end be
understood, whether defined entirely within the structures of the
proteins themselves or dependent on intermediary molecules. Just as the
known G
proteins fall into four classes based on similarities of
amino acid sequences, it seems likely that details of structural
determinants will define different types (categories) of functional
interactions of individual
and
subunits, receptors, effectors, and ancillary components. Although much remains to be
learned, it appears that at least some of these interactions depend
upon specific kinds of molecular complexes that are based upon
anchoring or scaffolding proteins such as those operative, for example,
in cAMP-dependent protein kinase (1) or G protein-coupled (2) signaling.
,
, and
subunits, receptors, ligands, and other components, which accounts for the inclusion of some more
complex terminology than one might wish. Because the story began in a
much simpler way, a bit of history may be useful or at least
interesting.
-adrenergic receptor, the first G protein-coupled
receptor with seven membrane-spanning
-helices to be
characterized.
s
(formerly Gs or Ns). Its subsequent purification and characterization by Gilman and co-workers, as well as
other studies in many laboratories, were facilitated by the
availability of cyc
cells that lack
G
s. These variant lymphoma cells were initially believed
to be deficient in adenylyl cyclase because they survived exposure to
agents that killed other lymphoma cells by increasing cAMP (11).
s.
s and
G
t (transducin) plus G
i and
G
o as well as the recognition that each of the other two
subunits, which are tightly associated as a
dimer, exists in
more than one form. In a classic review, Stryer and Bourne (13) were
able to synthesize a massive amount of data and suggest many of the
kinds of questions that had become accessible to investigation. They
predicted the imminent rewards from x-ray crystallographic analysis of
G protein structure and site-specific mutagenesis for functional
studies. A decade later much of this information is integrated in the
first review of this series entitled "The Many Faces of G Protein
Signaling" by Heidi E. Hamm, who has made major contributions in this
area.
-subunit; interactions with effectors or with unidentified
components may speed the kinetics of deactivation." In 1997, considerably more, albeit still incomplete, information was available,
some of which was summarized in a minireview by Dohlman and Thorner
(15). The second review of this series, "Mammalian RGS Proteins:
Barbarians at the Gate" by David M. Berman and Alfred G. Gilman,
brings the subject up-to-date from a slightly different
perspective.
as
well as
subunits and previously unrecognized effectors such as ion
channels and phospholipase C, were being elucidated with increasing
rapidity. Simultaneously, signal transduction from tyrosine kinase
receptors (e.g. for insulin and growth factors), including
Ras pathways with numerous other kinases and monomeric GTPases, was
enjoying increased experimental attention. Only relatively recently is
the extent to which these different pathways and their components
communicate and interact becoming apparent. J. Silvio Gutkind, who is
an important contributor to this progress, summarizes evidence for
"The Pathway Connecting G Protein-coupled Receptors to the Nucleus
through Divergent MAP Kinase Cascades" in the last review of this
series.
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FOOTNOTES |
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* This minireview will be reprinted in the 1996 Minireview Compendium, which will be available in December, 1996.
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