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J Biol Chem, Vol. 273, Issue 29, 17979-17982, July 17, 1998
From the
The majority of transmembrane signal
transduction in response to hormones and neurotransmitters is mediated
by G protein-coupled receptors
(GPCRs).1 Moreover, GPCRs are
the principal signal transducers for the senses of sight and smell.
GPCRs are characterized by seven membrane-spanning domains with an
extracellular N terminus and a cytoplasmic C terminus (Fig.
1) (GPCR structure reviewed in Refs.
1-3). Based on certain key sequences, GPCRs can be divided into three
major subfamilies, receptors related to rhodopsin (type A), receptors
related to the calcitonin receptor (type B), and receptors related to
the metabotropic receptors (type C). Of these, the rhodopsin subfamily is by far the largest and most extensively investigated and will be the
focus of the present review.
GPCR domains involved in ligand binding are nearly as diverse as the
chemical structures of the known agonists (1, 3, 5). Small molecular
weight ligands bind to sites within the hydrophobic core formed by the
transmembrane (TM) High resolution structural analysis of GPCRs has been hindered by their
low natural abundance and the difficulty in producing and purifying
significant quantities of recombinant protein. A low resolution
structure of rhodopsin obtained from electron diffraction of
two-dimensional crystals has been useful in predicting the arrangement
and relative orientation of the transmembrane domains (6, 7) (Fig.
2A). Mutagenesis studies aimed
at identifying intramolecular interactions have provided evidence for a
similar arrangement in other GPCRs (8-12), and several molecular
models of different GPCRs have been developed (13-15).
MINIREVIEW
G Protein-coupled Receptors
II. MECHANISM OF AGONIST
ACTIVATION*
and Department of Cellular Physiology, Institute
of Medical Physiology 12.5, The Panum Institute, University of
Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark and
§ Howard Hughes Medical Institute and Division of
Cardiovascular Medicine, Stanford University Medical School,
Stanford, California 94305
INTRODUCTION
Top
Introduction
References
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[in a new window]
Fig. 1.
Two-dimensional model of the 
2
receptor illustrating the key structural features of a GPCR belonging
to the "rhodopsin-like" subfamily. The most conserved residue
in each transmembrane segments is indicated both using the Schwartz
nomenclature (59) and the Ballesteros-Weinstein nomenclature (15). In
the Schwartz nomenclature the most conserved residue in each helix had
been given a generic number according to its position in the helix. In
the Ballesteros-Weinstein nomenclature the most conserved residue in
each helix had been given the number 50. A series of conserved
tryptophans and prolines are indicated in blue. The kink
that may be caused by ProVI:15 has been suggested to be critical for
the conformational changes involved in receptor activation (49). The
almost invariable disulfide bridge between extracellular loops 2 and 3 and the conserved palmitoylation site in the C-terminal tail are
indicated in white. Residues AspIII:08, SerV:12, SerV:16,
PheVI:17, and AsnVI:20 shown to be involved in binding of epinephrine
to the 2 adrenergic receptor are indicated in
red (3, 60). Mutations at Ala293
(green) in the 
1b receptor lead to
agonist-independent activation (31). Other residues are discussed in
the text.
-helices, whereas binding sites for peptides and
protein agonists include the N terminus and extracellular hydrophilic
loops joining the transmembrane domains (2, 5). Domains critical for
interaction with the G protein have been localized to the second and
third cytoplasmic loops and the C terminus (2).
View larger version (35K):
[in a new window]
Fig. 2.
A, arrangement of
transmembrane domains of a prototypical G protein-coupled receptor as
viewed from the extracellular surface of the membrane (based on the
projection maps from two-dimensional crystals of rhodopsin (7)).
B, proposed conformational changes in TM3 and TM6 following
agonist activation based on studies of rhodopsin and the
2 adrenergic receptor.
This review will examine current progress in addressing a fundamental question in the field of GPCR-mediated signal transduction: the nature of the physical changes in receptors that link agonist binding to G protein activation. It will explore the differences and similarities in the activation of rhodopsin and other GPCRs by focusing on two questions. What conformational changes take place during receptor activation? How do agonists induce these conformational changes in the receptor?
| |
Extended Ternary Complex Model |
|---|
Perhaps the most widely accepted model used to describe agonist activation of GPCRs is the ternary complex model, which accounts for the cooperative interactions among receptor, G protein, and agonist (16). This model has recently been extended to accommodate the observation that many receptors can activate G proteins in the absence of agonist and that mutations in different structural domains of the receptor can enhance this agonist-independent activity (17, 18). The extended ternary complex model also accounts for the effects of different classes of drugs (full agonists, partial agonists, neutral antagonists, and inverse agonists) on receptor signaling. The model proposes that the receptor exists in an equilibrium of two functionally distinct states: the inactive (R) and the active (R*) state. In the absence of agonists, the level of basal receptor activity is determined by the equilibrium between R and R*. The efficacy of ligands is thought to be a reflection of their ability to alter the equilibrium between these two states. Whereas most properties of GPCRs can be explained by this model, several studies suggest that a more complex model may be necessary (reviewed by Kenakin (19, 20)). Nevertheless, for the purpose of our discussion we will use the terms R to refer to the inactive conformation of the receptor and R* to refer to the conformation capable of activating G proteins.
| |
Agonist-induced Conformational Changes |
|---|
Is Dimerization Involved in Receptor
Activation?--
Agonist-induced receptor dimerization is required for
signal transduction for several non-GPCR receptor families having
single membrane-spanning domains (such as receptor tyrosine kinases and the growth hormone receptor family (21)). Several recent reports provide evidence that GPCRs can also form dimers, raising the possibility that dimerization is part of the activation process (22-24). However, different mechanisms of dimer formation were observed for different receptors (2 adrenergic receptor
(22), the 
-opioid receptor (23), and the metabotropic glutamate
receptor (24)) suggesting that receptor dimerization is not essential for G protein activation but may play a role in other receptor functions such as subtype-specific receptor regulation.
Evidence for Protonation as a Key Element in Receptor
Activation--
The conserved DRY motif at the cytoplasmic side of TM3
(Fig. 1, orange) is highly conserved in members of the
rhodopsin GPCR family (25). The invariably conserved arginine
(ArgIII:26) in this motif has been hypothesized to be constrained in a
hydrophilic pocket formed by conserved polar residues in TM1, TM2, and
TM7 (Fig. 1, yellow) (14, 26). It has been proposed that
receptor activation involves protonation of AspIII:25 causing
ArgIII:26 to shift out of the polar pocket leading to cytoplasmic
exposure of buried sequences in the second and third intracellular
loops. The hypothesis is supported both by computational simulations and by the observation that mutating AspIII:25 results in increased agonist-independent receptor activity of both the 1b
adrenergic receptor (14, 26) and the 2 adrenergic
receptor.2 Similarly,
mutation of the corresponding GluIII:25 in rhodopsin also causes
constitutive receptor activation (27, 28), and it has been demonstrated
that proton uptake by GluIII:25 in rhodopsin is an important event in
the formation of the activated metarhodopsin II intermediate (29).
GPCRs Are Maintained in an Inactive Conformation by Stabilizing
Intramolecular Interactions--
In several receptors it has been
demonstrated that discrete mutations in the C-terminal region of the
third intracellular loop can cause dramatic increases in
agonist-independent receptor activity (reviewed in Ref. 30).
Replacement of Ala293 in the 1b receptor
(Fig. 1, green) with any other residue resulted in higher
constitutive activity (31). It was therefore proposed that important
conformational constraints maintain the receptor preferentially in an
inactive conformation and that these constraint(s) are released upon
activation (or by specific mutations) causing key sequences to be
exposed to the G protein (30, 31). Recently, this hypothesis has been
supported by the observation that a mutation causing constitutive
activation of the 2 receptor is associated with a marked
structural instability and enhanced conformational flexibility
(32).
2 adrenergic receptor, providing additional support for an important role
of TM6 in the network of conformational constraints required to
maintain the receptor in the inactive state. A cysteine in TM6, which
is not accessible to modification by a charged hydrophilic sulfhydryl-specific reagent in the wild type 2 receptor,
becomes accessible in the constitutively active mutant (37). Further support for the importance of the orientation of TM6 relative to TM5
and TM3 in receptor activation comes from studies using engineered
metal ion binding sites. Histidine substitutions can be used to
generate a zinc-binding site between two TM domains. Zinc binding to
engineered metal ion binding sites linking TM6 and TM5 in the NK-1
(substance P) (38) and TM6 and TM3 in rhodopsin (39) prevented receptor
activation. A similar result was obtained by intramolecular disulfide
cross-linking between engineered pairs of cysteines in rhodopsin (40,
41).
Dissecting Specific Conformational Changes Involved in Receptor Activation-- Rhodopsin activation has been analyzed by different forms of spectroscopy including Fourier transform infrared resonance spectroscopy (42, 43), surface plasmon resonance spectroscopy (44), tryptophan UV absorbance spectroscopy (45), and EPR spectroscopy (41, 46, 47). All approaches have consistently provided evidence for significant conformational rearrangements accompanying transition of rhodopsin to metarhodopsin. Using tryptophan UV absorbance spectroscopy Sakmar and co-workers (45) were able to obtain evidence that photoactivation involves movement of TM3 relative to TM6. Further insight into the character of conformational changes in rhodopsin has been obtained by Khorana, Hubbell and co-workers (41, 46, 47) using EPR spectroscopy in combination with multiple cysteine substitutions. By site-selective incorporation of pairs of sulfhydryl-reactive spin labels in a series of double cysteine mutants they were able to measure changes in relative distance between TM3 and TM6 (41). The movement of TM3 was interpreted as being relatively small whereas the data pointed to a significant rigid-body movement of TM6 in a counterclockwise direction (when the TM is viewed from the extracellular surface of the receptor) and a movement of the cytoplasmic end of TM6 away from TM3 (41).
The use of fluorescence spectroscopic techniques in the2 adrenergic receptor has allowed the first direct
structural analysis of conformational changes in a ligand-activated
GPCR (32, 48, 49). The spectroscopic technique used in these studies
takes advantage of the sensitivity of many fluorescent molecules to the
polarity of their local molecular environment (48). The sulfhydryl-reactive fluorophore
N,N'-dimethyl-N-(iodoacetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-ethylenediamine (NBD) was used to label free cysteine residues in purified,
detergent-solubilized 2 adrenergic receptor (48). Both
the quantum yield of the emission spectrum and the limited
accessibility to hydrophilic quenchers strongly suggested that one or
more of the naturally occurring transmembrane cysteines was labeled
with the fluorophore. Exposure of NBD-labeled receptor to agonist led
to a reversible and dose-dependent decrease in fluorescence
emission consistent with movements of the fluorophore to a more
hydrophilic environment following binding of the full agonist
isoproterenol (48). Interestingly, exposure of the NBD-labeled receptor
to inverse agonists led to an apparent increase in fluorescence,
suggesting that not only agonists but also inverse agonists can promote
structural changes in a GPCR (48).
Spectral analysis of a series of mutant 2 receptors
having only one, two, or three of the natural cysteines available for fluorophore labeling showed that NBD bound to Cys125 in TM3
and to Cys285 in TM6 was responsible for the observed
agonist-induced changes in fluorescence (49). This suggests that
movements of TM3 and TM6 occur during receptor activation (49). In a
molecular model of the 2 receptor based on the
projection map of rhodopsin, the NBD attached to Cys125 is
bounded by the lipid bilayer and the interface of TM3 and TM4, whereas
the NBD attached to Cys285 is bounded by TM6 and TM7 and
the lipid bilayer (49). In the framework of this model the change in
fluorescence of NBD-labeled 2 receptor can best be
explained by a counterclockwise rotation (when viewed from the
extracellular side of the membrane) of both TM3 and TM6, which would
move the NBD molecules from the nonpolar lipid environment to the more
polar interior of the protein (49).
In summary, both biophysical and mutagenesis studies of rhodopsin and a
number of ligand-activated GPCRs provide evidence that the formation of
the R* state involves movements of TM3 and TM6. Fig.
2B illustrates the type of movement that would be predicted
from the spectroscopic studies of rhodopsin and the 2
adrenergic receptor (41, 49). It should be noted that these studies do
not exclude the possibility that other TMs or cytoplasmic domains
undergo significant movement during activation. Further investigation
will be required to provide a more detailed map of changes in GPCR
structure during activation.
| |
Mechanism of Agonist Activation |
|---|
The Mode of Activation of Rhodopsin Is Unique among GPCRs--
As
discussed above, experimental evidence suggests that the conformational
changes associated with activation of rhodopsin are similar to changes
associated with activation of ligand-activated GPCRs such as the
2 adrenergic receptor. However, the remarkable structural diversity among GPCR agonists (small molecules, peptides, and proteins) and the apparent lack of a common agonist-binding site
suggest that the mechanism by which agonists induce the activating conformational changes in GPCRs may differ significantly for different receptors (5). Rhodopsin is unique among the GPCRs in that its ligand
is covalently bound to the receptor as an inverse agonist and upon
absorption of a photon isomerizes to an agonist within the binding
pocket (reviewed by Sakmar (50)). Thus, the process of ligand binding
is not part of the activation process. This specialized mechanism of
activation may be necessary to facilitate the very rapid response of
rhodopsin to light. Conversion from the inverse agonist
cis-retinal to the full agonist trans-retinal occurs within femtoseconds of photon activation. Rhodopsin then rapidly
undergoes a series of conformational changes that have been
characterized spectroscopically (rhodopsin > bathorhodopsin > lumirhodopsin > metarhodopsin I > metarhodopsin II). The
structural changes associated with the formation of metarhodopsin II,
the R* form of rhodopsin, are observed within microseconds of photoactivation even in detergent solution in the absence of transducin (46). Metarhodopsin II then undergoes a slow
(t1/2 ~6 min) transition to the inactive
metarhodopsin III (46). This inactivating transition is associated with
the hydrolysis and release of trans-retinal from the binding
pocket (51). It is interesting that free trans-retinal is
not a very effective agonist for opsin (52, 53), producing only ~14%
of the response observed for light-activated rhodopsin (52). Thus, the
efficient activation of rhodopsin by trans-retinal requires
that the agonist be rapidly generated by photoisomerization of the
prebound inverse agonist cis-retinal. The less efficient
activation of opsin by free trans-retinal may more closely
reflect the process of activation of other GPCRs.
2 receptor in real time by fluorescence
spectroscopy (32, 48, 49). These studies were done under conditions
that are similar to those used to study conformational changes in
rhodopsin (in the detergent -dodecyl maltoside). In contrast to the
rapid activation and slow inactivation kinetics of rhodopsin, the
agonist-induced conformational changes observed in purified
2 adrenergic receptor are slow (t1/2 ~ 3 min) (48), even at agonist concentrations that would be predicted to ensure saturation of binding sites in less than 1 min (54). Reversal
of the agonist-induced conformation by antagonists is relatively rapid
(t1/2 ~30 s) (48). The differences in
activation kinetics between rhodopsin and the 2 receptor
may be influenced somewhat by the different methods used to monitor
conformational changes but most likely reflect fundamental differences
in the mechanism of activation by a covalently bound agonist
(trans-retinal) and a diffusible agonist
(isoproterenol).
Models of Activation by Diffusible Agonists--
The binding site
for catecholamines in the 2 adrenergic receptor is
remarkably similar to the binding site for retinal in rhodopsin (3,
50). The essential sites of interaction between catechol agonists and
the 2 adrenergic receptor are illustrated in Fig.
3A. Several models for the
interaction of ligands with their receptors have evolved from the study
of receptors, enzymes, and ligand-gated ion channels (55). The
2 adrenergic receptor is used to illustrate these models
in Fig. 3, B-D. "Ligand induction" (56), shown
mechanistically in Fig. 3B, predicts that transition from
the inactive to the active state is extremely rare in the absence of
agonist because of the energy barriers between R and
R*. The free energy of agonist binding to R is
used to overcome the energy barrier and facilitates (or induces) the
transition to R*. This model is consistent with the mechanism of activation of rhodopsin in that a photon rapidly converts
the inverse agonist cis-retinal to the agonist
trans-retinal, thereby inducing a rapid conformational
change in the protein. The model could also be used to explain the slow
agonist-induced conformational change observed for the 2
receptor by proposing a rapid association rate for agonist binding to
R and a slow rate for the transition from AR to
AR*. However, the model is inconsistent with the high basal
activity observed for many ligand-activated GPCRs, suggesting that the
energy barrier between R and R* is surmountable
in the absence of agonist.
|
2 adrenergic receptor. The model would predict that the
association rate for agonist binding is limited by the rate of
transition from R to R*, because agonist would
only bind to R*.
In limiting the number of conformational states to two (R
and R*), these models (Fig. 3, B and
C) fail to predict the observation that both agonists and
inverse agonists protect the 2 adrenergic receptor
against thermal denaturation (32) and proteolysis (58). These
experiments suggest that the unliganded receptor represents a distinct
state that is susceptible to denaturation and proteolysis, whereas the
conformations of the inverse agonist-bound state and the agonist-bound
state are both resistant.
Based on these observations a third model can be formulated (Fig.
3D). This model predicts that the unliganded receptor exists in a unique state R that can undergo transitions to at least
two other states, Ro and R*.
Ro is stabilized by inverse agonists, and
R* is stabilized by agonists. Mechanistically, this could be
explained by proposing that the unliganded receptor (R) is
not highly constrained by stabilizing intramolecular interactions and
is therefore more susceptible to thermal denaturation and proteolysis.
Moreover, R may undergo spontaneous transitions to the
R* state, explaining the high basal activity observed for
some GPCRs. As shown in Fig. 3D, binding of agonist domains
occurs sequentially, resulting in a series of conformational states
that are intermediates (R' and R") between
R and R*. As discussed above, results from
mutagenesis experiments indicate that 2 receptor agonists have several functionally important sites of interaction with
the receptor. Binding may involve an initial interaction between
receptor and one structural group of the agonist. Following the initial
binding of one structural group, binding of the remaining groups occurs
in a sequential manner as a result of random and spontaneous movements
of TM domains to positions that permit interaction with the functional
groups. Each interaction between the receptor and the agonist
stabilizes one or more TM domains until the receptor has been
stabilized in the active R* state. A similar mode of binding
can be envisioned for inverse agonists resulting in stabilization of
the Ro state. Partial agonists may stabilize one
of the intermediate states (R' or R"), thereby
increasing the chance of spontaneous isomerization to R*; or
they may stabilize unique conformational states having lower affinity
for the G protein. This model would be consistent both with a rapid
association rate for agonists (formation of AR') and the
relatively slow rate of conformational change observed
spectroscopically (formation of AR*). G proteins may
interact with the receptor to stabilize it in one of the intermediate
states (R' or R") and thereby influence both
agonist binding affinity and the kinetics of the conformational
change.
The model shown in Fig. 3 represents our best efforts to explain the
mechanism of GPCR activation with the limited experimental data
available. A more complete understanding of the molecular mechanism of
GPCR activation will require a high resolution structure, more detailed
information about the structural changes induced in the receptor by
different classes of ligands, and information from time-resolved
studies characterizing the sequence of conformational changes that
follow ligand binding.
| |
ACKNOWLEDGEMENTS |
|---|
We thank Pejman Ghanouni and Dr. Sansan Lin for critical reading of the manuscript, and Jason Kobilka for preparation of the figures.
| |
FOOTNOTES |
|---|
* This minireview will be reprinted in the 1998 Minireview Compendium, which will be available in December, 1998. This is the second article of three in the "G Protein-coupled Receptors Minireview Series." This work was supported in part by National Institutes of Health Grant RO 1 NS28471 and by the Harold G. and Leila Y. Mathers Charitable Foundation.
¶ To whom correspondence should be addressed: Howard Hughes Medical Inst., B157 Beckman Center, Stanford University Medical School, Stanford, CA 94305. Tel.: 650-723-7069; Fax: 650-498-5092; E-mail: kobilka{at}cmgm.stanford.edu.
1 The abbreviations used are: GPCR, G protein-coupled receptor; TM, transmembrane; NBD, N,N'-dimethyl-N-(iodoacetyl)-N'-(7-nitrobenz-2-oxa1,3-diazol-4-yl)-ethylenediamine.
2 S. Rasmussen, P. Ghanouni, A. D. Jensen, and U. Gether, manuscript in preparation.
| |
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R. Seifert Monovalent Anions Differentially Modulate Coupling of the beta 2-Adrenoceptor to Gsalpha Splice Variants J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 840 - 847. [Abstract] [Full Text] [PDF]
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G. Peleg, P. Ghanouni, B. K. Kobilka, and R. N. Zare Single-molecule spectroscopy of the beta 2 adrenergic receptor: Observation of conformational substates in a membrane protein PNAS, June 28, 2001; (2001) 151239698. [Abstract] [Full Text] [PDF]
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R. Seifert, K. Wenzel-Seifert, U. Gether, and B. K. Kobilka Functional Differences between Full and Partial Agonists: Evidence for Ligand-Specific Receptor Conformations J. Pharmacol. Exp. Ther., June 1, 2001; 297(3): 1218 - 1226. [Abstract] [Full Text]
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T. Nyrönen, M. Pihlavisto, J. M. Peltonen, A.-M. Hoffrén, M. Varis, T. Salminen, S. Wurster, A. Marjamäki, L. Kanerva, E. Katainen, et al. Molecular Mechanism for Agonist-Promoted alpha 2A-Adrenoceptor Activation by Norepinephrine and Epinephrine Mol. Pharmacol., April 16, 2001; 59(5): 1343 - 1354. [Abstract] [Full Text]
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G. Gimpl and F. Fahrenholz The Oxytocin Receptor System: Structure, Function, and Regulation Physiol Rev, April 1, 2001; 81(2): 629 - 683. [Abstract] [Full Text] [PDF]
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M. H. Wilson, H. A. Highfield, and L. E. Limbird The Role of a Conserved Inter-Transmembrane Domain Interface in Regulating {alpha}2a-Adrenergic Receptor Conformational Stability and Cell-Surface Turnover Mol. Pharmacol., April 1, 2001; 59(4): 929 - 938. [Abstract] [Full Text]
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F. X. Zhou, H. J. Merianos, A. T. Brunger, and D. M. Engelman Polar residues drive association of polyleucine transmembrane helices PNAS, February 8, 2001; (2001) 41593698. [Abstract] [Full Text]
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 D. Prou, W.-J. Gu, S. Le Crom, J.-D. Vincent, J. Salamero, and P. Vernier Intracellular retention of the two isoforms of the D2 dopamine receptor promotes endoplasmic reticulum disruption J. Cell Sci., January 10, 2001; 114(19): 3517 - 3527. [Abstract] [Full Text] [PDF]
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A. B. Fawzi, D. Macdonald, L. L. Benbow, A. Smith-Torhan, H. Zhang, B. C. Weig, G. Ho, D. Tulshian, M. E. Linder, and M. P. Graziano SCH-202676: An Allosteric Modulator of Both Agonist and Antagonist Binding to G Protein-Coupled Receptors Mol. Pharmacol., January 1, 2001; 59(1): 30 - 37. [Abstract] [Full Text]
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P. C. Dunlop, L. A. Leis, and G. J. Johnson Epinephrine correction of impaired platelet thromboxane receptor signaling Am J Physiol Cell Physiol, December 1, 2000; 279(6): C1760 - C1771. [Abstract] [Full Text] [PDF]
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M. de Gasparo, K. J. Catt, T. Inagami, J. W. Wright, and Th. Unger International Union of Pharmacology. XXIII. The Angiotensin II Receptors Pharmacol. Rev., September 1, 2000; 52(3): 415 - 472. [Abstract] [Full Text] [PDF]
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 T. Yokomizo, K. Kato, K. Terawaki, T. Izumi, and T. Shimizu A Second Leukotriene B4 Receptor, BLT2: A New Therapeutic Target in Inflammation and Immunological Disorders J. Exp. Med., August 8, 2000; 192(3): 421 - 432. [Abstract] [Full Text] [PDF]
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 M. Dosil, K. A. Schandel, E. Gupta, D. D. Jenness, and J. B. Konopka The C Terminus of the Saccharomyces cerevisiae alpha -Factor Receptor Contributes to the Formation of Preactivation Complexes with Its Cognate G Protein Mol. Cell. Biol., July 15, 2000; 20(14): 5321 - 5329. [Abstract] [Full Text]
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K. Kristiansen, W. K. Kroeze, D. L. Willins, E. I. Gelber, J. E. Savage, R. A. Glennon, and B. L. Roth A Highly Conserved Aspartic Acid (Asp-155) Anchors the Terminal Amine Moiety of Tryptamines and Is Involved in Membrane Targeting of the 5-HT2A Serotonin Receptor But Does Not Participate in Activation via a "Salt-Bridge Disruption" Mechanism J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 735 - 746. [Abstract] [Full Text]
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R. Brys, K. Josson, M. P. Castelli, M. Jurzak, P. Lijnen, W. Gommeren, and J. E. Leysen Reconstitution of the Human 5-HT1D Receptor-G-Protein Coupling: Evidence for Constitutive Activity and Multiple Receptor Conformations Mol. Pharmacol., June 1, 2000; 57(6): 1132 - 1141. [Abstract] [Full Text]
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S.-H. Lee, M.-y. Chang, K.-H. Lee, B. S. Park, Y.-S. Lee, H. R. Chin, and Y.-S. Lee Importance of Valine at Position 152 for the Substrate Transport and 2beta -Carbomethoxy-3beta -(4-fluorophenyl)tropane Binding of Dopamine Transporter Mol. Pharmacol., May 1, 2000; 57(5): 883 - 889. [Abstract] [Full Text]
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A. E. Alewijnse, H. Timmerman, E. H. Jacobs, M. J. Smit, E. Roovers, S. Cotecchia, and R. Leurs The Effect of Mutations in the DRY Motif on the Constitutive Activity and Structural Instability of the Histamine H2 Receptor Mol. Pharmacol., May 1, 2000; 57(5): 890 - 898. [Abstract] [Full Text]
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U. Maier, A. Babich, N. Macrez, D. Leopoldt, P. Gierschik, D. Illenberger, and B. Nurnberg Gbeta 5gamma 2 Is a Highly Selective Activator of Phospholipid-dependent Enzymes J. Biol. Chem., April 28, 2000; 275(18): 13746 - 13754. [Abstract] [Full Text] [PDF]
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 A. Lienhardt, M. Garabédian, M. Bai, C. Sinding, Z. Zhang, J.-P. Lagarde, J. Boulesteix, M. Rigaud, E. M. Brown, and M.-L. Kottler A Large Homozygous or Heterozygous In-Frame Deletion within the Calcium-Sensing Receptor's Carboxylterminal Cytoplasmic Tail That Causes Autosomal Dominant Hypocalcemia J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1695 - 1702. [Abstract] [Full Text]
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P. Ghanouni, H. Schambye, R. Seifert, T. W. Lee, S. G. F. Rasmussen, U. Gether, and B. K. Kobilka The Effect of pH on beta 2 Adrenoceptor Function. EVIDENCE FOR PROTONATION-DEPENDENT ACTIVATION J. Biol. Chem., February 4, 2000; 275(5): 3121 - 3127. [Abstract] [Full Text] [PDF]
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U. Gether Uncovering Molecular Mechanisms Involved in Activation of G Protein-Coupled Receptors Endocr. Rev., February 1, 2000; 21(1): 90 - 113. [Abstract] [Full Text]
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P. J. Pauwels, S. Tardif, T. Wurch, and F. C. Colpaert Facilitation of Constitutive alpha 2A-Adrenoceptor Activity by Both Single Amino Acid Mutation (Thr373Lys) and Galpha o Protein Coexpression: Evidence for Inverse Agonism J. Pharmacol. Exp. Ther., February 1, 2000; 292(2): 654 - 663. [Abstract] [Full Text]
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G. Krause, R. Hermosilla, A. Oksche, C. Rutz, W. Rosenthal, and R. Schülein Molecular and Conformational Features of a Transport-Relevant Domain in the C-Terminal Tail of the Vasopressin V2 Receptor Mol. Pharmacol., February 1, 2000; 57(2): 232 - 242. [Abstract] [Full Text]
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A. A. Konkar, Y. Zhai, and J. G. Granneman beta 1-Adrenergic Receptors Mediate beta 3-Adrenergic-Independent Effects of CGP 12177 in Brown Adipose Tissue Mol. Pharmacol., February 1, 2000; 57(2): 252 - 258. [Abstract] [Full Text]
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V. Behar, A. Bisello, G. Bitan, M. Rosenblatt, and M. Chorev Photoaffinity Cross-linking Identifies Differences in the Interactions of an Agonist and an Antagonist with the Parathyroid Hormone/Parathyroid Hormone-related Protein Receptor J. Biol. Chem., January 7, 2000; 275(1): 9 - 17. [Abstract] [Full Text] [PDF]
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N. I. Tarasova, W. G. Rice, and C. J. Michejda Inhibition of G-protein-coupled Receptor Function by Disruption of Transmembrane Domain Interactions J. Biol. Chem., December 3, 1999; 274(49): 34911 - 34915. [Abstract] [Full Text] [PDF]
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 B. J. Doranz, S. S. W. Baik, and R. W. Doms Use of a gp120 Binding Assay To Dissect the Requirements and Kinetics of Human Immunodeficiency Virus Fusion Events J. Virol., December 1, 1999; 73(12): 10346 - 10358. [Abstract] [Full Text]
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M. Blomenröhr, A. Heding, R. Sellar, R. Leurs, J. Bogerd, K. A. Eidne, and G. B. Willars Pivotal Role for the Cytoplasmic Carboxyl-Terminal Tail of a Nonmammalian Gonadotropin-Releasing Hormone Receptor in Cell Surface Expression, Ligand Binding, and Receptor Phosphorylation and Internalization Mol. Pharmacol., December 1, 1999; 56(6): 1229 - 1237. [Abstract] [Full Text]
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 S. F. Steinberg The Molecular Basis for Distinct {beta}-Adrenergic Receptor Subtype Actions in Cardiomyocytes Circ. Res., November 26, 1999; 85(11): 1101 - 1111. [Full Text] [PDF]
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K. Wenzel-Seifert, J. M. Arthur, H.-Y. Liu, and R. Seifert Quantitative Analysis of Formyl Peptide Receptor Coupling to Gialpha 1, Gialpha 2, and Gialpha 3 J. Biol. Chem., November 19, 1999; 274(47): 33259 - 33266. [Abstract] [Full Text] [PDF]
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S. D. C. Ward, C. A. M. Curtis, and E. C. Hulme Alanine-Scanning Mutagenesis of Transmembrane Domain 6 of the M1 Muscarinic Acetylcholine Receptor Suggests that Tyr381 Plays Key Roles in Receptor Function Mol. Pharmacol., November 1, 1999; 56(5): 1031 - 1041. [Abstract] [Full Text]
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 M. Honczarenko, R. S. Douglas, C. Mathias, B. Lee, M. Z. Ratajczak, and L. E. Silberstein SDF-1 Responsiveness Does Not Correlate With CXCR4 Expression Levels of Developing Human Bone Marrow B Cells Blood, November 1, 1999; 94(9): 2990 - 2998. [Abstract] [Full Text] [PDF]
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M. Waldhoer, A. Wise, G. Milligan, M. Freissmuth, and C. Nanoff Kinetics of Ternary Complex Formation with Fusion Proteins Composed of the A1-Adenosine Receptor and G Protein alpha -Subunits J. Biol. Chem., October 22, 1999; 274(43): 30571 - 30579. [Abstract] [Full Text] [PDF]
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A. J. Morris and C. C. Malbon Physiological Regulation of G Protein-Linked Signaling Physiol Rev, October 1, 1999; 79(4): 1373 - 1430. [Abstract] [Full Text] [PDF]
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J. S. Hayes, O. A. Lawler, M.-T. Walsh, and B. T. Kinsella The Prostacyclin Receptor Is Isoprenylated. ISOPRENYLATION IS REQUIRED FOR EFFICIENT RECEPTOR-EFFECTOR COUPLING J. Biol. Chem., August 20, 1999; 274(34): 23707 - 23718. [Abstract] [Full Text] [PDF]
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R. Seifert, U. Gether, K. Wenzel-Seifert, and B. K. Kobilka Effects of Guanine, Inosine, and Xanthine Nucleotides on beta 2-Adrenergic Receptor/Gs Interactions: Evidence for Multiple Receptor Conformations Mol. Pharmacol., August 1, 1999; 56(2): 348 - 358. [Abstract] [Full Text]
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