Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biological effects of hormones are mediated by plasma membrane receptors which transmit extracellular signals to the cytoplasm and nucleus. Mutations in plasma membrane receptors can affect normal signal transduction with loss-of-function mutations leading to hormone resistance and gain-of-function mutations leading to constitutive activation of signaling pathways. The loss-of-function mutations leading to familial hormone resistance disorders are germline in origin whereas the gain-of-function mutations leading to constitutively active receptors are somatic. G-protein coupled receptors (GPCR) comprise a large superfamily of proteins characterized by seven transmembrane-spanning segments and interaction with GTP-binding(G) proteins. Mutations in GPCRs have been associated with dwarfism, congenital hyperthyroidism or hypothyroidism, nephrogenic diabetes insipidus, obesity, resistance to TSH, LH, FSH and ACTH, Jansen's metaphyseal and Blomstrand's chondrodysplasia, autosomal dominant hypoparathyroidism, and neonatal severe hyperparathyroidism. Mutations in other families of receptors which are characterized into one spanning-transmembrane receptor can result in resistance to insulin, GH, leptin and AMH. This review summarizes the molecular defects in plasma membrane hormone receptors in a large number of clinical disorders.
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PMID:[Molecular defects in plasma membrane hormone receptors]. 1185 9

Aquaporins (AQPs) are a family of small hydrophobic, integral membrane proteins that are expressed in all living organisms and play critical roles in controlling the water flow into and out of cells. So far, 13 different AQPs have been identified in mammals (AQP 0-12). AQPs have recently been implicated in various diseases such as cancer, cataract, brain oedema, gallstone disease and nephrogenic diabetes insipidus, as well as in the development of obesity and polycystic kidney disease. Interfering with the expression of AQPs will undoubtedly have therapeutic applications. Hence, in this review, the authors look at each AQP and its association with various pathological conditions in humans and demonstrate that they form potential targets for the treatment of such diseases.
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PMID:Aquaporins: a promising target for drug development. 1710 75

There is considerable potential for translating knowledge of aquaporin structure, function and physiology to the clinic. One area is in aquaporin-based diagnostics. The discovery of AQP4 autoantibodies as a marker of the neuromyelitis optica form of multiple sclerosis has allowed precise diagnosis of this disease. Other aquaporin-based diagnostics are possible. Another area is in aquaporin-based genetics. Genetic diseases caused by loss-of-function mutations in aquaporins include nephrogenic diabetes insipidus and cataracts, and functionally significant aquaporin polymorphisms are beginning to be explored. Perhaps of greatest translational potential is aquaporin-based therapeutics. Information largely from aquaporin knockout mice has implicated key roles of aquaporin-facilitated water transport in transepithelial fluid transport (urinary concentrating, gland fluid secretion), water movement into and out of the brain, cell migration (angiogenesis, tumor metastasis, wound healing) and neural function (sensory signaling, seizures). A subset of aquaporins that transport both water and glycerol, the 'aquaglyceroporins', regulate glycerol content in epidermal, fat and other tissues, and are involved in skin hydration, cell proliferation, carcinogenesis and fat metabolism. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of edematous states, cancer, obesity, wound healing, epilepsy and glaucoma. These exciting possibilities and their associated challenges are reviewed.
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PMID:Aquaporins: translating bench research to human disease. 1944 80

The aquaporins are a family of membrane water channels, some of which also transport glycerol. They are involved in a wide range of physiological functions (including water/salt homeostasis, exocrine fluid secretion, and epidermal hydration) and human diseases (including glaucoma, cancer, epilepsy, and obesity). At the cellular level, aquaporin-mediated osmotic water transport across cell plasma membranes facilitates transepithelial fluid transport, cell migration, and neuroexcitation; aquaporin-mediated glycerol transport regulates cell proliferation, adipocyte metabolism, and epidermal water retention. Genetic diseases caused by loss-of-function mutations in aquaporins include nephrogenic diabetes insipidus and congenital cataracts. The neuroinflammatory demyelinating disease neuromyelitis optica is marked by pathogenic autoantibodies against astrocyte water channel aquaporin-4. There remain broad opportunities for the development of aquaporin-based diagnostics and therapeutics. Disease-relevant aquaporin polymorphisms are beginning to be explored. There is great promise in the development of small-molecule aquaporin modulators for therapy of some types of refractory edema, brain swelling, neuroinflammation, glaucoma, epilepsy, cancer, pain, and obesity.
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PMID:Aquaporins in clinical medicine. 2224 25

G protein-coupled receptors (GPCRs) are polytopic membrane proteins that have a pivotal role in cellular signaling. Like other membrane proteins, they fold in the endoplasmic reticulum (ER) before they are transported to the plasma membrane. The ER quality control monitors the folding process and misfolded proteins and slowly folding intermediates are targeted to degradation in the cytosol via the ubiquitin-proteasome pathway. The high efficiency of the quality control machinery may lead to the disposal of potentially functional receptors. This is the major underlying course for loss-of-function conformational diseases, such as retinitis pigmentosa, nephrogenic diabetes insipidus and early onset obesity, which involve mutant GPCRs. During the past decade, it has become increasingly evident that small-molecular lipophilic and pharmacologically selective receptor ligands, called pharmacological chaperones (PCs), can rescue these mutant receptors from degradation by stabilizing newly synthesized receptors in the ER and enhancing their transport to the cell surface. This has raised the interesting prospect that PCs might have therapeutic value for the treatment of conformational diseases. At the same time, accumulating evidence has indicated that wild-type receptors might also be targeted by PCs, widening their therapeutic potential. This review focuses on one GPCR subfamily, opioid receptors that have been useful models to unravel the mechanism of action of PCs. In contrast to most other GPCRs, compounds that act as PCs for opioid receptors, including widely used opioid drugs, target wild-type receptors and their common natural variants.
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PMID:Targeting opioid receptors with pharmacological chaperones. 2435 64

The aquaporins (AQPs) are a family of small, integral membrane proteins that facilitate water transport across the plasma membranes of cells in response to osmotic gradients. Data from knockout mice support the involvement of AQPs in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism, which suggests that modulation of AQP function or expression could have therapeutic potential in oedema, cancer, obesity, brain injury, glaucoma and several other conditions. Moreover, loss-of-function mutations in human AQPs cause congenital cataracts (AQP0) and nephrogenic diabetes insipidus (AQP2), and autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators include the druggability of the target and the suitability of the assay methods used to identify modulators.
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PMID:Aquaporins: important but elusive drug targets. 2462 25

The aim of this review is to present the research results and draw new conclusions about the impact of alterations in the signal transmission through the G protein-coupled receptors (GPCRs) on the formation of diseases and drug therapy. GPCR family is the largest and the most diverse group of membrane receptors. They transmit signals into the cell by interaction with different ligands, which include, inter alia, hormones, neurotransmitters, and photons. GPCRs are responsible for the proper conduction of many physiological processes such as vision, intercellular communication, the neuronal transmission, hormonal signaling and are involved in many pathological processes. They are also point on the binding pathway of multiple drugs. They are targets of nearly one third of the drugs at the current pharmaceutical market. The genes encoding GPCRs represent about 4% of the human genome. Mutations that occur in them are associated with a broad spectrum of diseases of diverse etiology. As a mutations result, there is a change in receptor activity (GPCR become inactive, overactive, or constitutively active), in the process of ligand binding and signal transduction. Changes in the GPCRs functioning can cause diseases such as retinitis pigmentosa (rhodopsin mutations), nephrogenic diabetes insipidus (vasopressin receptor mutations), obesity (melanocortin receptor mutations). Many mutational changes in genes encoding GPCR can change drug therapy of already existed diseases: heart failure (adrenergic receptors), asthma (cysteinyl leukotriene receptors). Studies concerning the structure and function of genetically modified GPCRs allow to get know a variety of mechanisms of its action, which in turn can contribute to broaden the knowledge on the etiology and pharmacotherapy of many currently incurable diseases.
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PMID:G protein-coupled receptors: abnormalities in signal transmission, disease states and pharmacotherapy. 2527 42

Congenital nephrogenic diabetes insipidus (NDI) is a conformation disease resulting from protein misfolding. Ninety percent of mutations result from the inactivating mutations of the arginine vasopressin receptor 2 (AVPR2) gene transmitted in an X-linked fashion, blocking the response to vasopressin, resulting in the inability to concentrate urine. Clinical features include polyuria, polydispsia, dehydration, and hypernatremia. They are generally more severely in affected males but present variably in females due to skewed inactivation of the X chromosome. We describe a case of a 40-year-old woman with a history of Type 2 diabetes mellitus, hyperlipidemia, and obesity, who presents with debilitating polyuria since the age of 5 with no clear diagnosis. Interestingly, her son was diagnosed with NDI. Genetic testing revealed that she was heterozygous for the Val88Met mutation in the AVPR2 gene while her son was hemizygous for the same. The patient has since been successfully treated with diuretics and a low solute diet. We highlight that although X-linked NDI patients are mostly males, it should be considered in symptomatic females to prevent delays in the diagnosis. Conformational diseases such as NDI are presently the subject of research using pharmacological chaperones to restore proper receptor membrane localization and function.
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PMID:A Rare Case of Congenital Diabetes Insipidus. 2621 64

Aquaporins (AQPs) are membrane channels widely distributed in human tissues. AQPs are essential for water and energy homeostasis being involved in a broad range of pathophysiological processes such as edema, brain injury, glaucoma, nephrogenic diabetes insipidus, salivary and lacrimal gland dysfunction, cancer, obesity and related metabolic complications. Compelling evidence indicates that AQPs are targets for therapeutic intervention with potential broad application. Nevertheless, efficient AQP modulators have been difficult to find due to either lack of selectivity and stability, or associated toxicity that hamper in vivo studies. MicroRNAs (miRNAs) are naturally occurring small non-coding RNAs that regulate post-transcriptional gene expression and are involved in several diseases. Recent identification of miRNAs as endogenous modulators of AQP expression provides an alternative approach to target these proteins and opens new perspectives for therapeutic applications. This mini-review compiles the current knowledge of miRNA interaction with AQPs highlighting miRNA potential for regulation of AQP-based disorders.
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PMID:The Emerging Role of microRNAs in Aquaporin Regulation. 2997 90