Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2009) 19 P149

SFEBES2009 Poster Presentations Diabetes, Metabolism and Cardiovascular (49 abstracts)

The Hsp90 chaperone machinery can modulate cell surface expression of the obesity linked G-protein coupled receptor MC4R

SB Gooljar , E Meimaridou & JP Chapple


Barts and the London School for Medicine and Dentistry, William Harvey Research Institute, Centre for Endocrinology, London, UK.


Mutations in the melanocortin-4 receptor (MC4R) are the most common cause of monogenic obesity. The majority of MC4R mutations are predicted to cause the receptor to aberrantly fold. Misfolded MC4R fails to traffic to the plasma membrane (PM) and is retained in the endoplasmic reticulum (ER). Recent studies with other G-protein coupled receptors have shown that stabilisation of misfolded receptor, by pharmacological chaperones, promotes trafficking to the cell surface where the receptor may be functional.

The main objective of this study was to develop a rapid throughput cell culture based assay to monitor MC4R trafficking to the PM. We are using this assay to screen pharmacological chaperones and drugs that target cellular molecular chaperones, for the ability to promote folding and cell surface expression of mutant MC4R.

We used laser scanning confocal microscopy to verify that a number of MC4R mutants co-localise with known ER proteins and do not transit to the PM. We have also developed a rapid throughput, plate based, cell culture, assay to monitor trafficking of epitope tagged MC4R. This assay confirmed clinically occurring MC4R mutants, including P78L, S58C, N62S, C271Y and P299H as intracellularly retained. We have identified that Hsp90 inhibitors modulates cell surface expression of wild-type and mutant MC4R. Furthermore, we have shown that heterologous expression of the Hsp90 co-chaperone Aha1, increases mutant MC4R cell surface expression and signalling of wild-type and mutant MC4R upon stimulation with ligand. Our data suggest the Hsp90 chaperone machinery may be a target for therapeutic intervention in disease where aberrant folding leads to disruption of normal GPCR trafficking.

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