AN INVESTIGATION INTO THE MOLECULAR MECHANISMS OF MELANIN-CONCENTRATING HORMONE R
Laurie B Cook
College At Brockport, Brockport, Ny 14420
Grant 3R15GM090163-01S1 from National Institute Of General Medical Sciences
Abstract: Melanin-concentrating hormone (MCH) mediates a variety of neurological functions including appetite and energy expenditure. The discovery of MCH receptors in peripheral tissues such as adipose tissue and pancreatic beta cells broadens the potential impact of this hormone on the whole-body response to food. Many cells desensitize following an initial round of hormone exposure to prevent over-stimulation of a particular signaling pathway. This desensitization typically involves receptor phosphorylation followed by ¿-arrestin recruitment and physical removal of the receptor from the plasma membrane via clathrin- mediated endocytosis. Alternatively, non-clathrin vesicles, such as caveolae, participate in agonist- mediated receptor endocytosis. Our lab´s preliminary data, in conjunction with studies published by other labs, suggest that both desensitizing pathways participate in the regulation of MCH signaling, however the molecular intricacies of each have yet to be worked out. This project specifically 1) characterizes the localization of MCHR1 to caveolae and establishes its impact of receptor function; 2) elucidates the involvement of agonist-induced phosphorylation and ¿-arrestin-2 recruitment in MCHR1 desensitization; and 3) maps the post-endocytic trafficking route of agonist-occupied MCHR1. The results from this work will impact the fields of receptor biology and appetite physiology. The experiments described are designed to enable the participation of undergraduate and Master´s research students choosing to engage in biomedical research training opportunities at our institution. Melanin-concentrating hormone regulates a wide range of physiological functions, the most widely known being appetite and energy expenditure. The experiments proposed herein are designed to provide us with detailed information regarding how MCH signaling is turned off, or desensitized, by cells. Abnormal MCH receptor desensitization mechanisms could result in excess appetite signaling and an obese phenotype. As we gain knowledge regarding the molecular basis for MCH signaling, novel pharmacological targets may be identified, and new medications may be developed in our fight against obesity
Keywords: Abscission; Adipose tissue; Agonist; Appetite; Arrestins; Biology; Biomedical Research; Body Tissues; Caveolae; Caveolas; Cell Communication and Signaling; Cell Signaling; Cell membrane; Cells; Chemotherapy-Hormones/Steroids; Clathrin; Cytoplasmic Membrane; Data; Desire for food; Drugs; Endocrine Gland Secretion; Endocytosis; Endosomes; Energy Expenditure; Energy Metabolism; Excision; Exposure to; Extirpation; Fatty Tissue; Food; GRK; Hormones; Institution; Intracellular Communication and Signaling; Investigation; Knowledge; Learning; Maps; Mediating; Medication; Molecular; Nature; Nervous System Physiology; Neurologic function; Neurological function; Obesity; Pancreatic beta Cell; Pathway interactions; Peripheral; Pharmaceutic Preparations; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physiologic; Physiological; Physiology; Plasma Membrane; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Protein Phosphorylation; Public Health; Publishing; Quelling; RNA Interference; RNA Silencing; RNA Silencings; RNAi; Receptor Protein; Receptosomes; Regulation; Removal; Research; Research Training; Role; Route; Sequence-Specific Posttranscriptional Gene Silencing; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Structure of beta Cell of islet; Students; Surgical Removal; Therapeutic Hormone; Tissues; Ubiquitilation; Ubiquitination; Ubiquitinoylation; VESCL; Vesicle; Work; adipose; adiposity; arrestin 2; base; biological signal transduction; corpulence; corpulency; corpulentia; desensitization; design; designing; drug/agent; experiment; experimental research; experimental study; fight against; melanin-concentrating hormone; melanin-concentrating hormone receptor; melanophore-concentrating hormone; melanosome concentrating hormone; nervous system function; novel; obese; obese people; obese person; obese population; pancreas beta cell; pathway; plasmalemma; prevent; preventing; public health medicine (field); public health relevance; receptor; receptor function; receptor internalization; receptor mediated endocytosis; receptor, MCH; receptor, melanine-concentrating hormone; research study; resection; response; sedentary; social role; trafficking; ubiquination; ubiquitin conjugation; white adipose tissue; yellow adipose tissue
Relevance: Relevance of the Proposed Work to Public Health Melanin-concentrating hormone regulates a wide range of physiological functions, the most widely known being appetite and energy expenditure. The experiments proposed herein are designed to provide us with detailed information regarding how MCH signaling is turned off, or desensitized, by cells. Abnormal MCH receptor desensitization mechanisms could result in excess appetite signaling and an obese phenotype. As we gain knowledge regarding the molecular basis for MCH signaling, novel pharmacological targets may be identified, and new medications may be developed in our fight against obesity
Project start date: 2010-09-01
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: PA-06-042
3R15GM090163-01S1 (2010): $36132
Sponsored Links Excellgen http://Excellgen.com
