Abstract
Calcineurin (protein phosphatase 3, Cn) is best known for its central position in Ca2+-dependent T-cell signaling. Interest in calcineurin has, however, conserved its momentum as new Ca2+-dependent pathways have been steadily surfacing in several other cell types, such as brain, heart, skin cells and beta pancreatic cells, and Cn appears to serve as a central controller of stress, immune response, and cellular proliferation and differentiation. Calcineurin is the principal target of the immunosuppressive drugs cyclosporin A (CsA) and tacrolimus (TRL). Therapy based on these immunosuppressants has markedly reduced the incidence of transplant rejection in allograft recipients. In addition, these drugs have proven very useful for patients suffering from chronic inflammatory skin conditions. Unfortunately, their application is somewhat limited by a broad spectrum of toxic side-effects, affecting several organ systems. This calls for enhancements in the design of this class of immunosuppressants. An intricate constellation of regulatory systems allows for precise modulation and adaptation of calcineurin activity in vivo. The last few years have been very fruitful in elucidating several long-standing issues regarding the binding patterns of substrates and inhibitors to Cn. This new knowledge may enable more precise manipulation of the Ca2+-calcineurin pathway in the near future, preferably targeted towards one specific substrate or cell system. In this review, we will discuss the factors and mechanisms underlying calcineurin activity regulation and their exploitation in recent approaches towards better immunosuppressants.
Keywords: Calcineurin, immunosuppressants, NFAT, RCAN, cyclosporin A (CsA), tacrolimus (TRL), CaM-binding domain, calpain, cardiomyocytes, Cn phosphatase activity, tacrolimus, phobic CnA, immunophilin, immunophilin complexes, inositol 1,4,5-triphosphate (IP3), Cyclosporin A, pimecrolimus, lipophilicity, topology, metalloenzyme, bovine brain, glycemic control, thioredoxin, phospholipids, arachidonic acid, polyphenolic aldehyde gossypol, protein phosphatase
Current Medicinal Chemistry
Title: Regulatory Mechanisms of Calcineurin Phosphatase Activity
Volume: 18 Issue: 2
Author(s): R. E.A. Musson and N. P.M. Smit
Affiliation:
Keywords: Calcineurin, immunosuppressants, NFAT, RCAN, cyclosporin A (CsA), tacrolimus (TRL), CaM-binding domain, calpain, cardiomyocytes, Cn phosphatase activity, tacrolimus, phobic CnA, immunophilin, immunophilin complexes, inositol 1,4,5-triphosphate (IP3), Cyclosporin A, pimecrolimus, lipophilicity, topology, metalloenzyme, bovine brain, glycemic control, thioredoxin, phospholipids, arachidonic acid, polyphenolic aldehyde gossypol, protein phosphatase
Abstract: Calcineurin (protein phosphatase 3, Cn) is best known for its central position in Ca2+-dependent T-cell signaling. Interest in calcineurin has, however, conserved its momentum as new Ca2+-dependent pathways have been steadily surfacing in several other cell types, such as brain, heart, skin cells and beta pancreatic cells, and Cn appears to serve as a central controller of stress, immune response, and cellular proliferation and differentiation. Calcineurin is the principal target of the immunosuppressive drugs cyclosporin A (CsA) and tacrolimus (TRL). Therapy based on these immunosuppressants has markedly reduced the incidence of transplant rejection in allograft recipients. In addition, these drugs have proven very useful for patients suffering from chronic inflammatory skin conditions. Unfortunately, their application is somewhat limited by a broad spectrum of toxic side-effects, affecting several organ systems. This calls for enhancements in the design of this class of immunosuppressants. An intricate constellation of regulatory systems allows for precise modulation and adaptation of calcineurin activity in vivo. The last few years have been very fruitful in elucidating several long-standing issues regarding the binding patterns of substrates and inhibitors to Cn. This new knowledge may enable more precise manipulation of the Ca2+-calcineurin pathway in the near future, preferably targeted towards one specific substrate or cell system. In this review, we will discuss the factors and mechanisms underlying calcineurin activity regulation and their exploitation in recent approaches towards better immunosuppressants.
Export Options
About this article
Cite this article as:
E.A. Musson R. and P.M. Smit N., Regulatory Mechanisms of Calcineurin Phosphatase Activity, Current Medicinal Chemistry 2011; 18 (2) . https://dx.doi.org/10.2174/092986711794088407
DOI https://dx.doi.org/10.2174/092986711794088407 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
-
COVID-19 Effects on Geriatric Population and Failures of Aminoquinoline
Therapy: Compilation of Studies from EU, USA, and China;
Safety and Efficacy of Vaccines in the Prevention and Treatment of
COVID-19
Current Medicinal Chemistry Capillary Degeneration and Right Ventricular Remodeling Due to Hypoxic Stress with Sugen5416
Current Vascular Pharmacology Mitochondrial Dysfunctions in Bipolar Disorder: Effect of the Disease and Pharmacotherapy
CNS & Neurological Disorders - Drug Targets Zinc, Metallothioneins and Longevity: Interrelationships with Niacin and Selenium
Current Pharmaceutical Design Atherogenesis in Renal Patients: A Model of Vascular Disease?
Current Vascular Pharmacology Atrial Fibrillation and Hypertension: “Quo Vadis”
Current Hypertension Reviews GDF11 Attenuated ANG II-Induced Hypertrophic Cardiomyopathy and Expression of ANP, BNP and Beta-MHC Through Down- Regulating CCL11 in Mice
Current Molecular Medicine A Review on Hematopoietic Stem Cell Treatment for Epilepsy
CNS & Neurological Disorders - Drug Targets The Hellp Syndrome: A Review
Current Women`s Health Reviews Editorial (Thematic Issue: The Long Way to a Successful Medical Therapy of Heart Failure with Beta-blockers in Children with Heart Disease)
Reviews on Recent Clinical Trials The Multi-modality Cardiac Imaging Approach to Cardiac Sarcoidosis
Current Medical Imaging Cardiac Metabolism in Diabetes Mellitus
Current Pharmaceutical Design Kinins as Therapeutic Agents in Cardiovascular and Renal Diseases
Current Pharmaceutical Design Coronary CT and the Coronary Calcium Score, the Future of ED Risk Stratification?
Current Cardiology Reviews Neuromuscular Disorders in Left Ventricular Hypertrabeculation/Noncompaction
Current Pharmaceutical Design Pathogenesis of Age-Related Cataract: A Systematic Review of Proteomic Studies
Current Proteomics Decreasing Systemic Toxicity Via Transdermal Delivery of Anticancer Drugs
Current Drug Metabolism INNO-206 (DOXO-EMCH), an Albumin-Binding Prodrug of Doxorubicin Under Development for Phase II Studies
Current Bioactive Compounds Refining the Indications of Implantable Cardioverter Defibrillator in Patients with Left Ventricular Dysfunction
Reviews on Recent Clinical Trials A Mitochondrial Approach to Cardiovascular Risk and Disease
Current Pharmaceutical Design