Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Neuron ; 87(1): 124-38, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-26074006

ABSTRACT

Chronic itch is a prevalent and debilitating condition for which few effective therapies are available. We harnessed the natural variation across genetically distinct mouse strains to identify transcripts co-regulated with itch behavior. This survey led to the discovery of the serotonin receptor HTR7 as a key mediator of serotonergic itch. Activation of HTR7 promoted opening of the ion channel TRPA1, which in turn triggered itch behaviors. In addition, acute itch triggered by serotonin or a selective serotonin reuptake inhibitor required both HTR7 and TRPA1. Aberrant serotonin signaling has long been linked to a variety of human chronic itch conditions, including atopic dermatitis. In a mouse model of atopic dermatitis, mice lacking HTR7 or TRPA1 displayed reduced scratching and skin lesion severity. These data highlight a role for HTR7 in acute and chronic itch and suggest that HTR7 antagonists may be useful for treating a variety of pathological itch conditions.


Subject(s)
Dermatitis, Atopic/genetics , Mice, Inbred C57BL/genetics , Mice, Inbred DBA/genetics , Pruritus/genetics , RNA, Messenger/metabolism , Receptors, Serotonin/genetics , Transient Receptor Potential Channels/genetics , Acute Disease , Animals , Chronic Disease , Dermatitis, Atopic/metabolism , Disease Models, Animal , Ganglia, Spinal/metabolism , Gene Expression Profiling , Humans , Mice , Mice, Inbred C57BL/metabolism , Mice, Inbred DBA/metabolism , Pruritus/chemically induced , Pruritus/metabolism , Receptors, Serotonin/drug effects , Receptors, Serotonin/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Serotonin/pharmacology , Serotonin Receptor Agonists/pharmacology , Selective Serotonin Reuptake Inhibitors/adverse effects , Selective Serotonin Reuptake Inhibitors/pharmacology , TRPA1 Cation Channel , Transient Receptor Potential Channels/drug effects , Transient Receptor Potential Channels/metabolism
2.
Apoptosis ; 20(5): 658-70, 2015 May.
Article in English | MEDLINE | ID: mdl-25682163

ABSTRACT

Maintenance of cellular homeostasis requires tight and coordinated control of numerous metabolic pathways, which are governed by interconnected networks of signaling pathways and energy-sensing regulators. Autophagy, a lysosomal degradation pathway by which the cell self-digests its own components, has over the past decade been recognized as an essential part of metabolism. Autophagy not only rids the cell of excessive or damaged organelles, misfolded proteins, and invading microorganisms, it also provides nutrients to maintain crucial cellular functions. Besides serving as essential structural moieties of biomembranes, lipids including sphingolipids are increasingly being recognized as central regulators of a number of important cellular processes, including autophagy. In the present review we describe how sphingolipids, with special emphasis on ceramides and sphingosine-1-phosphate, can act as physiological regulators of autophagy in relation to cellular and organismal growth, survival, and aging.


Subject(s)
Autophagy , Sphingolipids/metabolism , Animals , Biological Transport , Cell Membrane Permeability , Humans , Membrane Fusion
3.
PLoS One ; 8(7): e70087, 2013.
Article in English | MEDLINE | ID: mdl-23894595

ABSTRACT

Ceramide and its metabolites constitute a diverse group of lipids, which play important roles as structural entities of biological membranes as well as regulators of cellular growth, differentiation, and development. The C. elegans genome comprises three ceramide synthase genes; hyl-1, hyl-2, and lagr-1. HYL-1 function is required for synthesis of ceramides and sphingolipids containing very long acyl-chains (≥C24), while HYL-2 is required for synthesis of ceramides and sphingolipids containing shorter acyl-chains (≤C22). Here we show that functional loss of HYL-2 decreases lifespan, while loss of HYL-1 or LAGR-1 does not affect lifespan. We show that loss of HYL-1 and LAGR-1 functions extend lifespan in an autophagy-dependent manner, as knock down of the autophagy-associated gene ATG-12 abolishes hyl-1;lagr-1 longevity. The transcription factors PHA-4/FOXA, DAF-16/FOXO, and SKN-1 are also required for the observed lifespan extension, as well as the increased number of autophagosomes in hyl-1;lagr-1 animals. Both autophagic events and the transcription factors PHA-4/FOXA, DAF-16, and SKN-1 have previously been associated with dietary restriction-induced longevity. Accordingly, we find that hyl-1;lagr-1 animals display reduced feeding, increased resistance to heat, and reduced reproduction. Collectively, our data suggest that specific sphingolipids produced by different ceramide synthases have opposing roles in determination of C. elegans lifespan. We propose that loss of HYL-1 and LAGR-1 result in dietary restriction-induced autophagy and consequently prolonged longevity.


Subject(s)
Autophagy , Caenorhabditis elegans Proteins , Caenorhabditis elegans/enzymology , Caenorhabditis elegans/growth & development , Longevity , Oxidoreductases/deficiency , Animals , Autophagy/genetics , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Forkhead Transcription Factors , Gene Knockdown Techniques , Lipid Metabolism , Longevity/genetics , Oxidoreductases/genetics , Oxidoreductases/metabolism , Phenotype , Small Ubiquitin-Related Modifier Proteins/genetics , Small Ubiquitin-Related Modifier Proteins/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...