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Activation and endocytic internalization of melanocortin 3 receptor in neuronal cells
Author(s) -
Wachira James Munuhe,
Uradu Lawrence,
HughesDarden Cleo
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a116-a
Subject(s) - internalization , melanocortin , biology , insulin resistance , microbiology and biotechnology , melanocortin 3 receptor , melanocortins , endocytic cycle , endocrinology , g protein coupled receptor , protein kinase b , receptor , fyn , insulin receptor , medicine , signal transduction , melanocortin receptor , insulin , genetics , hormone , tyrosine kinase , endocytosis
Essential hypertension oftentimes clusters with obesity and insulin resistance but the mechanisms underlying the association are unknown. Studies with gene knockout mice have implicated autonomic melanocortin receptors, MC3R and MC4R, in the pathophysiology of obesity, insulin resistance and salt‐sensitive hypertension. In an attempt to better understand the mechanisms of function for these receptors, we expressed MC3R and MC4R in a neuronal background and demonstrated their colocalization to several membrane regions. In this study, we show that MC3R localizes to lipid rafts in neuronal cells and undergoes endocytic internalization upon activation through a kinase sensitive pathway. The appearance of the internalized receptor in lysosomes suggests that it is subsequently degraded. The expression of protein kinase A regulatory subunits and of c‐Jun and c‐Fos was analyzed by either immunoblotting or real‐time PCR. Although no discernable changes in the expression levels of these kinases was detected, an observed modification of a PKB responsive gene in MC3R expressing cells suggests an important role for the PI3K/AKT pathway in melanocortin mediated effects. Further, MC3R protein was localized to some cardiovascular centers of rat brain by immunohistochemistry and in the kidney by immunoblotting. These studies therefore suggest that cardiovascular effects of melanocortins arise from direct effects rather than secondarily to obesity and insulin resistance. Supported by MBRS‐Score grant #2SO6‐GM051971‐08 and RCMI grant # G12RR017581. Lawrence Uradu is supported by NIH/MARC grant #5T34GM007977‐21