Abstract
G protein-coupled receptors (GPCR) have generated considerable interest in the pharmaceutical industry as drug targets. Theories concerning antidepressant targets of action suggested pre-synaptic monoamine reuptake mechanisms regulating GPCR activities including delayed receptor desensitization and down-regulation. GRKs and β-arrestins translocate to the cell membrane and bind to agonist-occupied receptors. This uncouples these receptors from G proteins and promotes their internalization, leading to desensitization and down-regulation. Thus, GRKs and β-arrestins serve as negative regulators of GPCR signaling. Recently, GPCR have been demonstrated to elicit signals through interaction with β-arrestin as scaffolding proteins, independent of heterotrimeric G-protein coupling. β-arrestins function as scaffold proteins that interact with several cytoplasmic proteins and link GPCR to intracellular signaling pathways such as MAPK cascades. Recent work has also revealed that β-arrestins translocate from the cytoplasm to the nucleus and associatewith transcription cofactors such as p300 and CREB. They also interact with regulators of transcription factors. We review findings concerning effects of antidepressants on GRKs and β-arrestins and the plethora of antidepressants effects on signal transduction elements in which GRKs and β-arrestins serve as signaling scaffold proteins, and on transcription factors and cofactors in which β-arrestins mediate regulation of transcription. The emergence of G-protein-independent signaling pathways, through β-arrestins, changes the way in which GPCR signaling is evaluated, from a cell biological to a pharmaceutical perspective and raises the possibility for the development of pathway specific therapeutics e.g., antidepressant medications targeting GRKs and β-arrestin regulatory and signaling proteins.
Keywords: mood disorders, antidepressants, GPCR, GRK, β-arrestin
Current Pharmaceutical Design
Title: Antidepressants, β-Arrestins and GRKs: From Regulation of Signal Desensitization to Intracellular Multifunctional Adaptor Functions
Volume: 15 Issue: 14
Author(s): Moran Golan, Gabriel Schreiber and Sofia Avissar
Affiliation:
Keywords: mood disorders, antidepressants, GPCR, GRK, β-arrestin
Abstract: G protein-coupled receptors (GPCR) have generated considerable interest in the pharmaceutical industry as drug targets. Theories concerning antidepressant targets of action suggested pre-synaptic monoamine reuptake mechanisms regulating GPCR activities including delayed receptor desensitization and down-regulation. GRKs and β-arrestins translocate to the cell membrane and bind to agonist-occupied receptors. This uncouples these receptors from G proteins and promotes their internalization, leading to desensitization and down-regulation. Thus, GRKs and β-arrestins serve as negative regulators of GPCR signaling. Recently, GPCR have been demonstrated to elicit signals through interaction with β-arrestin as scaffolding proteins, independent of heterotrimeric G-protein coupling. β-arrestins function as scaffold proteins that interact with several cytoplasmic proteins and link GPCR to intracellular signaling pathways such as MAPK cascades. Recent work has also revealed that β-arrestins translocate from the cytoplasm to the nucleus and associatewith transcription cofactors such as p300 and CREB. They also interact with regulators of transcription factors. We review findings concerning effects of antidepressants on GRKs and β-arrestins and the plethora of antidepressants effects on signal transduction elements in which GRKs and β-arrestins serve as signaling scaffold proteins, and on transcription factors and cofactors in which β-arrestins mediate regulation of transcription. The emergence of G-protein-independent signaling pathways, through β-arrestins, changes the way in which GPCR signaling is evaluated, from a cell biological to a pharmaceutical perspective and raises the possibility for the development of pathway specific therapeutics e.g., antidepressant medications targeting GRKs and β-arrestin regulatory and signaling proteins.
Export Options
About this article
Cite this article as:
Golan Moran, Schreiber Gabriel and Avissar Sofia, Antidepressants, β-Arrestins and GRKs: From Regulation of Signal Desensitization to Intracellular Multifunctional Adaptor Functions, Current Pharmaceutical Design 2009; 15 (14) . https://dx.doi.org/10.2174/138161209788168038
DOI https://dx.doi.org/10.2174/138161209788168038 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Rho Kinase and Angiogenesis
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Translational Multimodality Neuroimaging
Current Drug Targets The Role of Carrier Geometry in Overcoming Biological Barriers to Drug Delivery
Current Pharmaceutical Design Targeting Angiogenesis for Treatment of NSCLC Brain Metastases
Current Cancer Drug Targets Hypoxia in DU-145 Prostate Cancer Xenografts after Estramustine Phosphate and Radiotherapy
Current Radiopharmaceuticals Chemoinformatics in Multi-target Drug Discovery for Anti-cancer Therapy: In Silico Design of Potent and Versatile Anti-brain Tumor Agents
Anti-Cancer Agents in Medicinal Chemistry Inhibition of Angiogenesis as a Treatment Strategy for Neuroblastoma
Current Cancer Therapy Reviews Development of <sup>18</sup>F-Labeled PET Probes for Imaging Cell Proliferation
Current Topics in Medicinal Chemistry Omega-3 Polyunsaturated Fatty Acid Derived Lipid Mediators and their Application in Drug Discovery
Current Medicinal Chemistry Update on Cancer Related Issues of Mesenchymal Stem Cell-Based Therapies
Current Stem Cell Research & Therapy Physiopathological Roles of P2X Receptors in the Central Nervous System
Current Medicinal Chemistry Highlights in Peptide Nanoparticle Carriers Intended to Oral Diseases
Current Topics in Medicinal Chemistry Boronated Compounds for Imaging Guided BNCT Applications
Anti-Cancer Agents in Medicinal Chemistry Nanomedicines as Therapeutics in HIV-AIDS
Pharmaceutical Nanotechnology A New Twist in Cellular Resistance to the Anticancer Drug Bleomycin-A5
Current Drug Metabolism Cerebral Arachidonate Cascade in Dementia: Alzheimers Disease and Vascular Dementia
Current Neuropharmacology Isolation, Purification and Characterization of a Novel Steroidal Saponin Cholestanol Glucoside from Lasiodiplodia theobromae that Induces Apoptosis in A549 Cells
Anti-Cancer Agents in Medicinal Chemistry GPR55 and its Interaction with Membrane Lipids: Comparison with Other Endocannabinoid-Binding Receptors
Current Medicinal Chemistry Non-viral Gene Delivery and Therapeutics Targeting to Brain
Current Nanoscience A Review on Anti-urease Potential of Coumarins
Current Drug Targets