scholarly journals Getting the message across: Pathophysiology and signaling via receptors for polypeptide hormones and proteinases

2010 ◽  
Vol 33 (2) ◽  
pp. 133 ◽  
Author(s):  
Morley D Hollenberg
Keyword(s):  
Drug Targets ◽  
Time Span ◽  
Activation Mechanism ◽  
Therapeutic Implications ◽  
Proteinase Activated Receptors ◽  
Tethered Ligand ◽  
Polypeptide Hormones ◽  
G Protein Coupled ◽  
Receptor Family

This article provides a personalized overview of the role of proteinases in generating hormone-like cell signals. Also outlined is the unexpected route of discovery that led one investigator over a four-decade time span, from early studies of the interactions of oxytocin and vasopressin with their neurophysin binding proteins to current studies of the tethered ligand activation mechanism that is unique for the G-protein-coupled family of proteinase-activated receptors (PARs). The focus is not only on the intriguing PAR receptor family, but also on alternative mechanisms whereby proteinases activate signal transduction pathways. Also summarized are the potential physiological and pathophysiological roles that PARs may play in the setting of inflammatory disorders ranging from arthritis to colitis. The therapeutic implications of considering PARs as drug targets are also discussed.

scholarly journals Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors

2021 ◽  
Vol 8 ◽  
Author(s):  
Giuseppe Deganutti ◽  
Silvia Atanasio ◽  
Roxana-Maria Rujan ◽  
Patrick M. Sexton ◽  
Denise Wootten ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Approved Drugs ◽  
G Protein Coupled ◽  
Dynamic Docking ◽  
Receptor Family

Class B1 G protein-coupled receptors (GPCRs) are important targets for many diseases, including cancer, diabetes, and heart disease. All the approved drugs for this receptor family are peptides that mimic the endogenous activating hormones. An understanding of how agonists bind and activate class B1 GPCRs is fundamental for the development of therapeutic small molecules. We combined supervised molecular dynamics (SuMD) and classic molecular dynamics (cMD) simulations to study the binding of the calcitonin gene-related peptide (CGRP) to the CGRP receptor (CGRPR). We also evaluated the association and dissociation of the antagonist telcagepant from the extracellular domain (ECD) of CGRPR and the water network perturbation upon binding. This study, which represents the first example of dynamic docking of a class B1 GPCR peptide, delivers insights on several aspects of ligand binding to CGRPR, expanding understanding of the role of the ECD and the receptor-activity modifying protein 1 (RAMP1) on agonist selectivity.

scholarly journals Role of GPER-Mediated Signaling in Testicular Functions and Tumorigenesis

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2115
Author(s):  
Adele Chimento ◽  
Arianna De Luca ◽  
Marta Claudia Nocito ◽  
Paola Avena ◽  
Davide La Padula ◽  
...  
Keyword(s):  
Leydig Cells ◽  
Somatic Cells ◽  
Estrogen Signaling ◽  
Specific Cell ◽  
Cell Type ◽  
Cancer Cell Growth ◽  
Testicular Cells ◽  
G Protein Coupled ◽  
Receptor Family

Estrogen signaling plays important roles in testicular functions and tumorigenesis. Fifteen years ago, it was discovered that a member of the G protein-coupled receptor family, GPR30, which binds also with high affinity to estradiol and is responsible, in part, for the rapid non-genomic actions of estrogens. GPR30, renamed as GPER, was detected in several tissues including germ cells (spermatogonia, spermatocytes, spermatids) and somatic cells (Sertoli and Leydig cells). In our previous review published in 2014, we summarized studies that evidenced a role of GPER signaling in mediating estrogen action during spermatogenesis and testis development. In addition, we evidenced that GPER seems to be involved in modulating estrogen-dependent testicular cancer cell growth; however, the effects on cell survival and proliferation depend on specific cell type. In this review, we update the knowledge obtained in the last years on GPER roles in regulating physiological functions of testicular cells and its involvement in neoplastic transformation of both germ and somatic cells. In particular, we will focus our attention on crosstalk among GPER signaling, classical estrogen receptors and other nuclear receptors involved in testis physiology regulation.

scholarly journals Drug Repurposing on G Protein-Coupled Receptors Using a Computational Profiling Approach

2021 ◽  
Vol 8 ◽  
Author(s):  
Alessandra de Felice ◽  
Simone Aureli ◽  
Vittorio Limongelli
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Chemical Properties ◽  
Drug Repurposing ◽  
G Protein Coupled Receptors ◽  
Alignment Algorithm ◽  
Binding Interaction ◽  
Wide Range ◽  
G Protein Coupled ◽  
Receptor Family

G protein-coupled receptors (GPCRs) are the largest human membrane receptor family regulating a wide range of cell signaling. For this reason, GPCRs are highly desirable drug targets, with approximately 40% of prescribed medicines targeting a member of this receptor family. The structural homology of GPCRs and the broad spectrum of applications of GPCR-acting drugs suggest an investigation of the cross-activity of a drug toward different GPCR receptors with the aim of rationalizing drug side effects, designing more selective and less toxic compounds, and possibly proposing off-label therapeutic applications. Herein, we present an original in silico approach named “Computational Profiling for GPCRs” (CPG), which is able to represent, in a one-dimensional (1D) string, the physico-chemical properties of a ligand–GPCR binding interaction and, through a tailored alignment algorithm, repurpose the ligand for a different GPCR. We show three case studies where docking calculations and pharmacological data confirm the drug repurposing findings obtained through CPG on 5-hydroxytryptamine receptor 2B, beta-2 adrenergic receptor, and M2 muscarinic acetylcholine receptor. The CPG code is released as a user-friendly graphical user interface with numerous options that make CPG a powerful tool to assist the drug design of GPCR ligands.

scholarly journals Two protonation switches control rhodopsin activation in membranes

2008 ◽  
Vol 105 (46) ◽  
pp. 17795-17800 ◽  
Author(s):  
Mohana Mahalingam ◽  
Karina Martínez-Mayorga ◽  
Michael F. Brown ◽  
Reiner Vogel
Keyword(s):  
Transmembrane Domain ◽  
Conformational Transition ◽  
Salt Bridge ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Partial Activation ◽  
Ph Dependent ◽  
G Protein Coupled ◽  
Receptor Conformation ◽  
Receptor Family

Activation of the G protein-coupled receptor (GPCR) rhodopsin is initiated by light-induced isomerization of the retinal ligand, which triggers 2 protonation switches in the conformational transition to the active receptor state Meta II. The first switch involves disruption of an interhelical salt bridge by internal proton transfer from the retinal protonated Schiff base (PSB) to its counterion, Glu-113, in the transmembrane domain. The second switch consists of uptake of a proton from the solvent by Glu-134 of the conserved E(D)RY motif at the cytoplasmic terminus of helix 3, leading to pH-dependent receptor activation. By using a combination of UV–visible and FTIR spectroscopy, we study the activation mechanism of rhodopsin in different membrane environments and show that these 2 protonation switches become partially uncoupled at physiological temperature. This partial uncoupling leads to ≈50% population of an entropy-stabilized Meta II state in which the interhelical PSB salt bridge is broken and activating helix movements have taken place but in which Glu-134 remains unprotonated. This partial activation is converted to full activation only by coupling to the pH-dependent protonation of Glu-134 from the solvent, which stabilizes the active receptor conformation by lowering its enthalpy. In a membrane environment, protonation of Glu-134 is therefore a thermodynamic rather than a structural prerequisite for activating helix movements. In light of the conservation of the E(D)RY motif in rhodopsin-like GPCRs, protonation of this carboxylate also may serve a similar function in signal transduction of other members of this receptor family.

Proteinase-mediated cell signalling: targeting proteinase-activated receptors (PARs) by kallikreins and more

2006 ◽  
Vol 387 (6) ◽  
pp. 677-685 ◽  
Author(s):  
Katerina Oikonomopoulou ◽  
Kristina K. Hansen ◽  
Mahmoud Saifeddine ◽  
Nathalie Vergnolle ◽  
Illa Tea ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Physiological Responses ◽  
Cell Signalling ◽  
Target Cells ◽  
Serine Proteinases ◽  
Catalytic Domains ◽  
Proteinase Activated Receptors ◽  
G Protein Coupled ◽  
Unique Mechanism ◽  
Receptor Family

AbstractSerine proteinases, like trypsin, can play a hormone-like role by triggering signal transduction pathways in target cells. In many respects these hormone-like actions of proteinases can now be understood in terms of the pharmacodynamics of the G protein-coupled ‘receptor’ responsible for the cellular actions of thrombin (proteinase-activated receptor-1, or PAR1). PAR1, like the other three members of this receptor family (PAR2, PAR3and PAR4), has a unique mechanism of activation involving the proteolytic unmasking of an N-terminally tethered sequence that can activate the receptor. The selective activation of each PAR by short synthetic peptides representing these sequences has demonstrated that PAR1, PAR2and PAR4play important roles in regulating physiological responses ranging from vasoregulation and cell growth to inflammation and nociception. We hypothesise that the tissue kallikreins may regulate signal transduction via the PARs. Although PARs can account for many of their biological actions, kallikreins may also cause effects by mechanisms not involving the PARs. For instance, trypsin activates the insulin receptor and thrombin can act via a mechanism involving its non-catalytic domains. Based on the data we summarise, we propose that the kallikreins, like thrombin and trypsin, must now be considered as important ‘hormonal’ regulators of tissue function.

scholarly journals Ubiquitylation of nuclear receptors: new linkages and therapeutic implications

2015 ◽  
Vol 54 (3) ◽  
pp. R151-R167 ◽  
Author(s):  
Kyle T Helzer ◽  
Christopher Hooper ◽  
Shigeki Miyamoto ◽  
Elaine T Alarid
Keyword(s):  
Nuclear Receptors ◽  
Targeted Therapies ◽  
Drug Targets ◽  
Transcriptional Regulators ◽  
Receptor Function ◽  
Therapeutic Implications ◽  
Clinical Challenge ◽  
Entry Points ◽  
Therapeutic Development

The nuclear receptor (NR) superfamily is a group of transcriptional regulators that control multiple aspects of both physiology and pathology and are broadly recognized as viable therapeutic targets. While receptor-modulating drugs have been successful in many cases, the discovery of new drug targets is still an active area of research, because resistance to NR-targeting therapies remains a significant clinical challenge. Many successful targeted therapies have harnessed the control of receptor activity by targeting events within the NR signaling pathway. In this review, we explore the role of NR ubiquitylation and discuss how the expanding roles of ubiquitin could be leveraged to identify additional entry points to control receptor function for future therapeutic development.

scholarly journals Mentors And The Butterfly Effect: Triggers For Discovering Signalling by Proteinases via Proteinase-Activated Receptors (PARs) And More

2012 ◽  
Vol 35 (6) ◽  
pp. 378
Author(s):  
Morley D Hollenberg
Keyword(s):  
Inflammatory Disease ◽  
Cell Function ◽  
Cell Signalling ◽  
The Novel ◽  
Molecular Pharmacology ◽  
Proteinase Activated Receptors ◽  
Butterfly Effect ◽  
The One ◽  
G Protein Coupled

The essential role of proteinases as regulatory digestive enzymes, recognized since the late 1800s, has been underscored by the discovery that more than 2% of the genome codes for proteinases and their inhibitors. Further, by the early 1970s it was appreciated that in addition to their digestive actions, proteinases can affect cell function: (1) by the generation or degradation of peptide hormones and (2) by the direct regulation of signalling by receptors like the one for insulin. It was the discovery in the 1990s of the novel G-protein-coupled ‘proteinase-activated receptor’ (PAR) family that has caused a paradigm shift in the understanding of the way that proteinases can regulate cell signalling. This overview provides a perspective for the discovery of the PARs and my laboratory’s role in (1) understanding the molecular pharmacology of these fascinating receptors and (2) identifying the potential pathophysiological roles that the PAR family can play in inflammatory disease. In this context, the overview also portrays the essential impact that seemingly minor comments/insights provided by my lifelong mentors have had on kindling my intense interest in proteinase-mediated signalling. The ‘butterfly effect’ of those comments has led to an unexpectedly large impact on my own research directions. Hopefully my own ‘butterfly comments’ will also be heard by my trainees and other colleagues with whom I am currently working and will promote future discoveries that will be directly relevant to the treatment of inflammatory disease.

scholarly journals Crystal structure of β-arrestin 2 in complex with an atypical chemokine receptor phosphopeptide reveals an alternative active conformation

2019 ◽  
Author(s):  
Kyungjin Min ◽  
Hye-Jin Yoon ◽  
Ji Young Park ◽  
Mithu Baidya ◽  
Hemlata Dwivedi ◽  
...  
Keyword(s):  
Crystal Structure ◽  
G Protein ◽  
Chemokine Receptors ◽  
Drug Targets ◽  
Antibody Fragment ◽  
Structural Features ◽  
Activation Mechanism ◽  
Active Conformation ◽  
Hydrogen Deuterium ◽  
G Protein Coupled

Abstractβ-arrestins (βarrs) critically regulate signaling and trafficking of G protein-coupled receptors (GPCRs), the largest family of drug targets in the human genome, and there are two isoforms of βarrs: βarr1 and βarr2. Most GPCRs interact with both the heterotrimeric G-proteins and βarrs, inducing distinct downstream signal transduction. However, certain chemokine receptors lack functional G-protein coupling, but they can efficiently recruit βarrs upon agonist-stimulation, and they are referred to as atypical chemokine receptors (ACKRs). Receptor phosphorylation is a key determinant for the binding of βarrs, and understanding the intricate details of receptor-βarr interaction is the next frontier in GPCR structural biology. To date, the high-resolution structures of active βarr1 have been revealed, but the activation mechanism of βarr2 by a phosphorylated GPCR remains elusive. Here, we present a 1.95 Å crystal structure of βarr2 in complex with a phosphopeptide (C7pp) derived from the carboxyl-terminus of ACKR3, also known as CXCR7. The structure of C7pp-bound βarr2 reveals key differences from the previously determined active conformation of βarr1. One of the key differences is that C7pp-bound βarr2 shows a relatively small inter-domain rotation. An antibody-fragment-based conformational sensor and hydrogen/deuterium exchange experiments further corroborate structural features and suggest that the determined structure is an alternative active conformation of βarr2.

Proteinase-activated receptors: novel mechanisms of signaling by serine proteases

1998 ◽  
Vol 274 (6) ◽  
pp. C1429-C1452 ◽  
Author(s):  
Olivier Déry ◽  
Carlos U. Corvera ◽  
Martin Steinhoff ◽  
Nigel W. Bunnett
Keyword(s):  
G Proteins ◽  
Serine Proteases ◽  
G Protein Coupled Receptors ◽  
Parallel Mechanisms ◽  
New Family ◽  
Proteinase Activated Receptors ◽  
Degradative Enzymes ◽  
Tethered Ligand ◽  
G Protein Coupled ◽  
Efficient Mechanisms

Although serine proteases are usually considered to act principally as degradative enzymes, certain proteases are signaling molecules that specifically regulate cells by cleaving and triggering members of a new family of proteinase-activated receptors (PARs). There are three members of this family, PAR-1 and PAR-3, which are receptors for thrombin, and PAR-2, a receptor for trypsin and mast cell tryptase. Proteases cleave within the extracellular NH2-terminus of their receptors to expose a new NH2-terminus. Specific residues within this tethered ligand domain interact with extracellular domains of the cleaved receptor, resulting in activation. In common with many G protein-coupled receptors, PARs couple to multiple G proteins and thereby activate many parallel mechanisms of signal transduction. PARs are expressed in multiple tissues by a wide variety of cells, where they are involved in several pathophysiological processes, including growth and development, mitogenesis, and inflammation. Because the cleaved receptor is physically coupled to its agonist, efficient mechanisms exist to terminate signaling and prevent uncontrolled stimulation. These include cleavage of the tethered ligand, receptor phosphorylation and uncoupling from G proteins, and endocytosis and lysosomal degradation of activated receptors.

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