Structural insights into adrenergic receptor function and pharmacology

doi:10.1016/j.tips.2011.02.005

Trends in Pharmacological Sciences

Volume 32, Issue 4, April 2011, Pages 213-218

https://doi.org/10.1016/j.tips.2011.02.005 Get rights and content

It has been over 50 years since Sir James Black developed the first beta adrenergic receptor (βAR) blocker to treat heart disease. At that time, the concept of cell surface receptors was relatively new and not widely accepted, and most of the tools currently used to characterize plasma membrane receptors had not been developed. There has been remarkable progress in receptor biology since then, including the development of radioligand binding assays, the biochemical characterization of receptors as discrete membrane proteins, and the cloning of the first G-protein-coupled receptors (GPCRs), which led to the identification of other members of the large family of GPCRs. More recently, progress in GPCR structural biology has led to insights into the three-dimensional structures of βARs in both active and inactive states. Despite all of this progress, the process of developing a drug for a particular GPCR target has become more complex, time-consuming and expensive.

Section snippets

Adrenergic receptor subtypes and complex signaling behavior

When Sir James Black and colleagues developed propranolol, the scope of adrenergic receptor pharmacology was limited to two subtypes: alpha (α) and beta (β) adrenergic receptors. Catecholamines induced vasoconstriction through αARs and increased heart rate and contraction through βARs. Since then, nine adrenergic receptor genes have been identified (IUPHAR database: http://www.iuphar-db.org/DATABASE/GPCRListForward): α1AAR, α1BAR, α1DAR, α2AAR, α2BAR, α2CAR, β1AR, β2AR and β3AR. The β2AR has

More than just beta blockers

The idea of ligand efficacy was proposed by Stephenson in 1956 [20]. At the time Sir James was developing propranolol, ligands fell into three categories: full agonists, partial agonists and antagonists or blockers. Full agonists are drugs that maximally activate the receptor in a signaling assay (either direct G protein activation or activation of an effector protein regulated by a G protein), whereas partial agonists produce submaximal activity even at saturating concentrations. The concept

GPCR structural biology

Two- and three-dimensional crystal structures of rhodopsin purified from bovine retina provided the first three-dimensional images of GPCRs 27, 28, 29. However, hormone-activated GPCRs proved to be more challenging subjects for structural studies owing to the lack of a naturally abundant source of protein, as well as their inherent structural instability, and the relatively small amount of structured polar surface available for forming crystal lattice contacts. Three approaches have been used

Structural insights into subtype selectivity

The β1AR and β2AR structures provided the first high-resolution picture of the ligand-binding pocket of an adrenergic receptor, and the first insight into the challenges involved in developing subtype-selective ligands. Figure 2a shows the binding pocket of the human β2AR. Only one of the 15 amino acids that constitute the antagonist binding pocket (defined as being within 4 Å of the inverse agonist carazol) differs between β1AR and β2AR. Tyr308 at the top of TM7 in the β2AR is Phe in the β1AR.

Structural changes upon activation

Opinions on activation of GPCRs have evolved considerably over the past two decades. Early models consisted of two receptor states: an inactive state (R) in equilibrium with an active state (R*) [39]. In these models, the level of receptor activity depends on the effect of ligands on this equilibrium (R ⇆ R*), with agonists and partial agonists shifting the equilibrium to the right, and inverse agonists shifting the equilibrium to the left. Although many aspects of GPCR function can be explained

The impact of structural biology on GPCR drug discovery

Structural biology has been an integral part of drug discovery for soluble proteins such as kinases and proteases [49], and will probably play a role in the development of drugs for GPCRs. However, there are important differences in the time required to obtain crystal structures and the ability to manipulate crystals. The value of a crystal structure in drug development is greatest when it is available early in the discovery process so that crystals might be used for fragment-based screens and

References (51)

S.K. Shenoy
beta-Arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor
J. Biol. Chem.
(2006)
T.E. Hebert
A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation
J. Biol. Chem.
(1996)
T.H. Bayburt
Transducin activation by nanoscale lipid bilayers containing one and two rhodopsins
J. Biol. Chem.
(2007)
A.J. Kuszak
Purification and functional reconstitution of monomeric mu-opioid receptors: allosteric modulation of agonist binding by Gi2
J. Biol. Chem.
(2009)
M.R. Whorton
Efficient coupling of transducin to monomeric rhodopsin in a phospholipid bilayer
J. Biol. Chem.
(2008)
S. Banerjee
Rapid incorporation of functional rhodopsin into nanoscale apolipoprotein bound bilayer (NABB) particles
J. Mol. Biol.
(2008)
T. Kenakin
Ligand-selective receptor conformations revisited: the promise and the problem
Trends Pharmacol. Sci.
(2003)
J.D. Violin et al.
Beta-arrestin-biased ligands at seven-transmembrane receptors
Trends Pharmacol. Sci.
(2007)
T.P. Kenakin
7TM receptor allostery: putting numbers to shapeshifting proteins
Trends Pharmacol. Sci.
(2009)
V.M. Unger et al.
Low resolution structure of bovine rhodopsin determined by electron cryo-microscopy
Biophys. J.
(1995)

J. Li

Structure of bovine rhodopsin in a trigonal crystal form

J. Mol. Biol.

(2004)

S. Faham et al.

Bicelle crystallization: a new method for crystallizing membrane proteins yields a monomeric bacteriorhodopsin structure

J. Mol. Biol.

(2002)

C. Riekel

Protein crystallography microdiffraction

Curr. Opin. Struct. Biol.

(2005)

S. Suryanarayana

Identification of intramolecular interactions in adrenergic receptors

J. Biol. Chem.

(1992)

P. Leff

The two-state model of receptor activation

Trends Pharmacol. Sci.

(1995)

P. Ghanouni

Functionally different agonists induce distinct conformations in the G protein coupling domain of the beta 2 adrenergic receptor

J. Biol. Chem.

(2001)

G. Liapakis

The forgotten serine. A critical role for Ser2035.42 in ligans binding to and activation of the beta 2-adrenergic receptor

J. Biol. Chem.

(2000)

M. Sabio

Use of the X-ray structure of the beta2-adrenergic receptor for drug discovery. Part 2: identification of active compounds

Bioorg. Med. Chem. Lett.

(2008)

R.J. Lefkowitz

Seven transmembrane receptors: something old, something new

Acta Physiol. (Oxf.)

(2007)

R.A. Dixon

Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin

Nature

(1986)

R.A. Dixon

Structural features required for ligand binding to the beta-adrenergic receptor

EMBO J.

(1987)

B.K. Kobilka

Chimeric alpha 2-,beta 2-adrenergic receptors: delineation of domains involved in effector coupling and ligand binding specificity

Science

(1988)

S.G. Rasmussen

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor

Nature

(2007)

D.M. Rosenbaum

GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function

Science

(2007)

Y. Daaka

Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A

Nature

(1997)

Cited by (159)

Brown adipose tissue-derived metabolites and their role in regulating metabolism
2024, Metabolism: Clinical and Experimental
The discovery and rejuvenation of metabolically active brown adipose tissue (BAT) in adult humans have offered a new approach to treat obesity and metabolic diseases. Beyond its accomplished role in adaptive thermogenesis, BAT secretes signaling molecules known as “batokines”, which are instrumental in regulating whole-body metabolism via autocrine, paracrine, and endocrine action. In addition to the intrinsic BAT metabolite-oxidizing activity, the endocrine functions of these molecules may help to explain the association between BAT activity and a healthy systemic metabolic profile. Herein, we review the evidence that underscores the significance of BAT-derived metabolites, especially highlighting their role in controlling physiological and metabolic processes involving thermogenesis, substrate metabolism, and other essential biological processes. The conversation extends to their capacity to enhance energy expenditure and mitigate features of obesity and its related metabolic complications. Thus, metabolites derived from BAT may provide new avenues for the discovery of metabolic health-promoting drugs with far-reaching impacts. This review aims to dissect the complexities of the secretory role of BAT in modulating local and systemic metabolism in metabolic health and disease.
The stress connection in cancer: the adrenergic fuelling of breast tumors
2023, Current Opinion in Physiology
Cancer progression involves complex interactions between tumor cells and the surrounding microenvironment. Chronic psychosocial stress and sympathetic nervous system activation lead to abnormal catecholamine release, impacting tumor cells directly and indirectly and fuelling cancer-promoting effects. However, the same adrenergic Receptor (AR) that mediate these effects could also convey exercise-related beneficial changes. Epidemiological studies show conflicting associations between stress, AR inhibitors, and breast cancer (BC) metastatic progression. Adrenergic sympathetic stress triggers sustained inflammatory and hypoxic-related signaling pathways, alters function and distribution of immune cell populations, and remodels blood vessels, leading to immunosuppression and premetastatic site formation. Activated AR initiate feedback loops with tyrosine kinase receptors and chemokine receptors, affecting stem-related transcription factors, pro-inflammatory mediators, angiogenic factors, and energy metabolism regulators, promoting tumor growth and invasion. Understanding molecular mechanisms of agonistic and antagonistic AR ligands and crosstalk with other signaling pathways is crucial for developing effective therapies targeting adrenergic-driven BC progression.
Intramolecular activity regulation of adhesion GPCRs in light of recent structural and evolutionary information
2023, Pharmacological Research
The class B2 of GPCRs known as adhesion G protein-coupled receptors (aGPCRs) has come under increasing academic and nonacademic research focus over the past decade due to their physiological importance as mechano-sensors in cell-cell and cell-matrix contexts. A major advance in understanding signal transduction of aGPCRs was achieved by the identification of the so-called Stachel sequence, which acts as an intramolecular agonist at the interface between the N terminus (Nt) and the seven-transmembrane helix domain (7TMD). Distinct extracellular signals received by the Nt are integrated at the Stachel into structural changes of the 7TMD towards an active state conformation. Until recently, little information was available on how the activation process of aGPCRs is realized at the molecular level. In the past three years several structures of the 7TMD plus the Stachel in complex with G proteins have been determined, which provide new insights into the architecture and molecular function of this receptor class. Herein, we review this structural information to extract common and distinct aGPCR features with particular focus on the Stachel binding site within the 7TMD. Our analysis extends the current view of aGPCR activation and exposes similarities and differences not only between diverse aGPCR members, but also compared to other GPCR classes.
Chronic unpredictable stress induces depression/anxiety-related behaviors and alterations of hippocampal monoamine receptor mRNA expression in female mice at different ages
2023, Heliyon
Depression and anxiety are the most common mental health disorders. Though they affect people at any age and occur more often in females, the pathophysiological changes under these conditions are less investigated. In the present study, we examined the effects of age and stress on depression- and anxiety-related behaviors in female mice. Saccharin preference and the open field test were carried out before and after chronic unpredictable stress in 4-, 14- and 25-month-old female mice. After behavioral tests, mRNA levels of monoamine receptors in the hippocampus were measured by real-time RT-PCR. Chronic unpredictable stress decreased saccharin preference in 4-, 14- and 25-month-old mice and the time spent in the center in the open field test in 25-month-old mice. For monoamine receptors, analysis of variance revealed significant effects of age on mRNA levels of Htr1a, Htr2a, Htr6, Adra1a, Adrb2, and Adrb3, significant effects of stress on mRNA levels of Htr4, Adra2c, Adrb1, and Adrb2, and interactions of age × stress on mRNA levels of Htr1a, Htr5b, Adra1d, Adra2a, Adra2c, and Adrb1. Chronic unpredictable stress decreased mRNA levels of Htr4, Htr5b, Adra2c, and Adrb1 in 4-month-old female mice. Correlations were observed between saccharin preference and mRNA levels of Htr4, Htr5b, Htr6, Adra1d, Adra2a, and Adra2c in 4-month-old mice and between the time spent in the center in the open field test and mRNA levels of Htr1b in 4-month-old mice, Htr3a, Htr7, and Adrb2 in 14-month-old mice, and Drd2 in 4- and 14-month-old mice. Our findings support that stress induces depression- and anxiety-related behaviors and the expression of hippocampal monoamine receptors in an age-dependent manner in female mice.
Rational design, synthesis, and pharmacological evaluation of a cohort of novel beta-adrenergic receptors ligands enables an assessment of structure-activity relationships
2023, European Journal of Medicinal Chemistry
Biomedical applications of molecules that are able to modulate β-adrenergic signaling have become increasingly attractive over the last decade, revealing that β-adrenergic receptors (β-ARs) are key targets for a plethora of therapeutic interventions, including cancer. Despite successes in β-AR drug discovery, identification of β-AR ligands that are useful as selective chemical tools in pharmacological studies of the three β-AR subtypes, or lead compounds for drug development is still a highly challenging task. This is mainly due to the intrinsic plasticity of β-ARs as G protein-coupled receptors in conjunction with the requirement for functional receptor subtype selectivity, tissue specificity and minimal off-target effects. With the aim to provide insight into structure-activity relationships for the three β-AR subtypes, we have synthesized and obtained the pharmacological profile of a series of structurally diverse compounds (named MC) that were designed based on the aryloxy-propanolamine scaffold of SR59230A. Comparative analysis of their predicted binding mode within the active and inactive states of the receptors in combination with their pharmacological profile revealed key structural elements that control their activity as agonists or antagonists, in addition to clues about substituents that mediate selectivity for one receptor subtype over the others. We anticipate that these results will facilitate selective β-AR drug development efforts.
Human C1orf27 protein interacts with α<inf>2A</inf>-adrenergic receptor and regulates its anterograde transport
2022, Journal of Biological Chemistry
The molecular mechanisms underlying the anterograde surface transport of G protein–coupled receptors (GPCRs) after their synthesis in the endoplasmic reticulum (ER) are not well defined. In C. elegans, odorant response abnormal 4 has been implicated in the delivery of olfactory GPCRs to the cilia of chemosensory neurons. However, the function and regulation of its human homolog, C1orf27, in GPCR transport or in general membrane trafficking remain unknown. Here, we demonstrate that siRNA-mediated knockdown of C1orf27 markedly impedes the ER-to-Golgi export kinetics of newly synthesized α_2A-adrenergic receptor (α_2A-AR), a prototypic GPCR, with the half-time being prolonged by more than 65%, in mammalian cells in retention using the selective hooks assays. Using modified bioluminescence resonance energy transfer assays and ELISAs, we also show that C1orf27 knockdown significantly inhibits the surface transport of α_2A-AR. Similarly, C1orf27 knockout by CRISPR-Cas9 markedly suppresses the ER–Golgi-surface transport of α_2A-AR. In addition, we demonstrate that C1orf27 depletion attenuates the export of β₂-AR and dopamine D2 receptor but not of epidermal growth factor receptor. We further show that C1orf27 physically associates with α_2A-AR, specifically via its third intracellular loop and C terminus. Taken together, these data demonstrate an important role of C1orf27 in the trafficking of nascent GPCRs from the ER to the cell surface through the Golgi and provide novel insights into the regulation of the biosynthesis and anterograde transport of the GPCR family members.

View all citing articles on Scopus

View full text

Trends in Pharmacological Sciences

ReviewStructural insights into adrenergic receptor function and pharmacology

Section snippets

Adrenergic receptor subtypes and complex signaling behavior

More than just beta blockers

GPCR structural biology

Structural insights into subtype selectivity

Structural changes upon activation

The impact of structural biology on GPCR drug discovery

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Mol. Biol.

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

Biophys. J.

J. Mol. Biol.

J. Mol. Biol.

Curr. Opin. Struct. Biol.

J. Biol. Chem.

Trends Pharmacol. Sci.

J. Biol. Chem.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

Seven transmembrane receptors: something old, something new

Acta Physiol. (Oxf.)

Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin

Nature

Structural features required for ligand binding to the beta-adrenergic receptor

EMBO J.

Chimeric alpha 2-,beta 2-adrenergic receptors: delineation of domains involved in effector coupling and ligand binding specificity

Science

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor

Nature

GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function

Science

Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A

Nature

Review
Structural insights into adrenergic receptor function and pharmacology