Activation and Endocytic Internalization of Melanocortin 3 Receptor in Neuronal Cells

:  Melanocortins play a central role in autonomic modulation of metabolism by acting through a family of highly homologous G protein–coupled receptors. Studies with gene knockout mice have implicated neural melanocortin receptors, MC3R and MC4R, in the etiology of obesity, insulin resistance, and sa...

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Bibliographic Details
Published in:Annals of the New York Academy of Sciences 2007-01, Vol.1096 (1), p.271-286
Main Authors: WACHIRA, S. J. M., GURUSWAMY, B., URADU, L., HUGHES-DARDEN, C. A., DENARO, F. J.
Format: Article
Language:English
Subjects:
Animals
Endocytosis
Enzyme Activation
Gene Expression Regulation
Insulin Resistance
melanocortin 3 receptor
Membrane Microdomains
Mice
Neurons - metabolism
protein kinase C
Protein Kinase C - metabolism
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Receptor, Melanocortin, Type 3 - biosynthesis
Receptors, G-Protein-Coupled
supraoptic nucleus
Supraoptic Nucleus - metabolism
γ-MSH
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Summary::  Melanocortins play a central role in autonomic modulation of metabolism by acting through a family of highly homologous G protein–coupled receptors. Studies with gene knockout mice have implicated neural melanocortin receptors, MC3R and MC4R, in the etiology of obesity, insulin resistance, and salt‐sensitive hypertension. In an attempt to better understand the mechanisms of function of these receptors, we expressed MC3R and MC4R in neuronal cells and demonstrated their co‐localization to several membrane regions. We now show that in cultured neuronal cells, MC3R localizes to lipid rafts and undergoes endocytic internalization upon activation by γ‐MSH through a protein 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. No discernable changes were observed in the expression levels of these protein kinase A and protein kinase C responsive genes. Immunohistochemical studies showed a robust expression of MC3R protein in brain nuclei with relevance to cardiovascular function and fluid homeostasis further supporting the notion that the physiological effects of melanocortins on the cardiovascular system arise from effects on the central nervous system.
ISSN:0077-8923
1749-6632
DOI:10.1196/annals.1397.093