From the Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892
Several months ago the current understanding of
some specific aspects of "Signaling by Heterotrimeric G Proteins"
was summarized in a series of minireviews by some of those working most
actively in the field. Although three quite different topics were
addressed, there was an attempt to emphasize overall similarities of
structure and function among the numerous If the diversity and complexity of G protein interactions is daunting,
the universe of G protein-coupled receptors, more than 1000 of which
are known, could be considered overwhelming. Thanks to the efforts of a
great many investigators, however, it is becoming possible to
rationalize the enormous amount of available data in a way that is
yielding a perception of underlying parallels (and differences) in
their interactions with activating ligands, as well as with effectors
and other molecules that modulate their activity or serve in a
scaffolding/anchoring capacity. This issue of the Journal contains the
first of a series of three minireviews on "Signaling by G
Protein-coupled Receptors." It is hoped that they will provide an
interesting and informative overview of these critical molecules.
The first G protein-coupled receptors to be purified and characterized
were rhodopsin, the photon receptor from retinal rod outer segments,
and the The first minireview by Tae H. Ji, Mathis Grossmann, and Inhae Ji on
"Diversity of Receptor-Ligand Interactions" summarizes briefly the
overall three-dimensional structure of G protein-coupled receptors in
cell membranes as background for the more detailed consideration of
individual subfamilies. The latter are defined by differences in the
kinds of agonist ligands with which they interact. The agonists range
widely in size and structure from large glycoprotein hormones to
relatively simple amines or nucleosides and even cations. Differences
in receptor structure and mechanisms of ligand interaction then further
characterize the subfamilies. This seems to be a useful (and
enlightening) way of thinking about the multitude of G protein-coupled
receptors.
Present knowledge of the conformational changes in G protein-coupled
receptors that link agonist binding to G protein activation is
described in the second minireview, "Mechanism of Agonist
Activation," by Ulrik Gether and Brian K. Kobilka. They have focused
on the rhodopsin-like receptors, which are the best known and appear to
represent the largest family of G protein-coupled receptors. The model
presented, along with the summary of experimental approaches employed
to obtain data from which the three-dimensional molecular structure can
be deduced, should facilitate understanding of current thinking about
how these molecules transduce signals from the external environment to
the G proteins that will, in turn, communicate with the effector.
The third minireview is an update on "New Roles for Receptor Kinases
and
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- and
-subunits and
to provide an organizational framework within which subgroups of
specific subunits could be considered and compared.
-adrenergic receptor. They were the fruits of completely
independent research efforts, directed on the one hand toward
understanding the mechanism of light activation of cGMP
phosphodiesterase and on the other toward the mechanism of activation
of adenylyl cyclase by epinephrine. Differences in the agonists
(catecholamines and photons) and effectors (adenylyl cyclase and cGMP
phosphodiesterase) provided an early hint of the remarkable diversity
of situations in which G protein-coupled receptors are employed to
select, amplify, and transmit signals from the external environment to
elicit cellular responses and modify functions. As a result of cDNA
cloning, the structural resemblance of these two G protein-coupled
receptors with seven membrane-spanning helices was established, and
cloning made possible the subsequent extraordinarily rapid accumulation
of information on other members of the family. More recently, notable
advances in methodology and techniques of structural biology have
facilitated studies in several laboratories that provide new details of
mechanisms of agonist binding and initiation or transmission of
signals, as well as the orientation and translocation of specific parts of the receptor molecule relative to the lipid bilayer membrane in
which it resides.
-Arrestins in Receptor Signaling and Desensitization." Phosphorylation of the receptor catalyzed by these specific kinases with resulting modification of its association with other proteins and
its subcellular localization underlies the relatively rapid desensitization (as opposed to the slower down-regulation) or alteration of receptor function. Termination of activation and desensitization of receptors are, of course, as much a part of their
regulatory function as the initiation and transmission of signals. An
exciting product of the studies reviewed, however, is the realization
that reactions hitherto viewed solely as parts of a mechanism for
receptor desensitization may be equally important in signaling by G
protein-coupled receptors, thereby increasing the potential scope and
complexity of their physiological roles. The author, Robert J. Lefkowitz, continues to be a major contributor in this area, as he was
in the purification and cloning of the
-adrenergic receptor in the
1980s.
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* This minireview will be reprinted in the 1998 Minireview Compendium, which will be available in December, 1998.