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
-
State of the Heart: CMR in Coronary Artery Disease
Current Medical Imaging Protein Misfolding Diseases and Therapeutic Approaches
Current Protein & Peptide Science Myocardial Structure and Matrix Metalloproteinases
Current Topics in Medicinal Chemistry Fused 1,4-Dihydropyridines as Potential Calcium Modulatory Compounds
Mini-Reviews in Medicinal Chemistry Mesenchymal Stem Cells: A Good Candidate for Restenosis Therapy?
Current Vascular Pharmacology Classification of Heart Disease Using MFO Based Neural Network on MRI Images
Current Medical Imaging PPARγ Activation Improves the Molecular and Functional Components of Ito Remodeling by Angiotensin II
Current Pharmaceutical Design Hydrogen Sulfide in Diabetic Complications: Focus on Molecular Mechanisms
Endocrine, Metabolic & Immune Disorders - Drug Targets Emerging Potential of Natural Products as an Alternative Strategy to Pharmacological Agents Used Against Metabolic Disorders
Current Drug Metabolism Evaluation of the Antioxidant and Antidiabetic Potential of the Poly Herbal Formulation: Identification of Bioactive Factors
Cardiovascular & Hematological Agents in Medicinal Chemistry Cardiac and Pulmonary Manifestations in the Antiphospholipid Syndrome
Current Rheumatology Reviews Advances in Chagas Disease Chemotherapy
Anti-Infective Agents in Medicinal Chemistry In Silico Approach to Finding New Active Compounds from Histone Deacetylase (HDAC) Family
Current Pharmaceutical Design Determinants of Left Ventricular Hypertrophy
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Oxidative and Inflammatory Events in Prion Diseases: Can They Be Therapeutic Targets?
Current Aging Science Gender Related Issues in the Management of Heart Failure
Current Pharmaceutical Design Sleep-Disordered Breathing and Cardiovascular Disease: Exploring Pathophysiology and Existing Data
Current Respiratory Medicine Reviews Metformin and Anti-Cancer Therapeutics: Hopes for a More Enhanced Armamentarium Against Human Neoplasias?
Current Medicinal Chemistry Medicinal Chemistry of Drugs Used in Diabetic Cardiomyopathy
Current Medicinal Chemistry The Role of Molecular Imaging in the Assessment of Cardiac Amyloidosis: State-of-the-Art
Current Radiopharmaceuticals