Bouvier and colleagues describe how membrane-permeable G-protein-coupled receptor (GPCR) ligands can facilitate maturation and endoplasmic reticulum export of GPCRs, a phenomenon that could have significant implications for drugs that target GPCRs and other membrane proteins.
Quality control of newly synthesized membrane proteins, such as G-protein-coupled receptors (GPCRs), in the endoplasmic reticulum (ER) is important in ensuring that only properly folded proteins reach the cell surface. Even subtle mutations that would not markedly affect protein function can lead to ER retention and subsequent degradation of the mutant protein, which can have adverse results; for example, nephrogenic diabetes insipidus (NDI) is caused by such mutations in the V2 vasopressin receptor (V2R). Moreover, it also seems that a proportion of newly synthesized non-mutant proteins might never attain their correct structure owing to inefficient processing and therefore be degraded. As Petäjä-Repo, Bouvier and colleagues describe in The EMBO Journal, membrane-permeable GPCR ligands can facilitate maturation and ER export of GPCRs, a phenomenon that could have significant implications for drugs that target GPCRs and other membrane proteins.
Prompted by previous experiments that had shown that membrane-permeable antagonists of the V2R could functionally rescue several receptor mutants that were normally retained in the ER, the authors studied the effects of various opioid ligands on the maturation and ER export of the opioid receptor, which is known to be inefficiently processed. Naltrexone — a membrane-permeable antagonist — doubled the amount of mature receptors, an effect that was shown not to be due to an influence on protein synthesis or on stabilization of proteins at the cell surface.
Other membrane-permeable opioid antagonists and agonists also favoured maturation of the opioid receptor, but a membrane-permeable antagonist of the unrelated V2R did not, indicating that receptor occupancy is required to influence receptor maturation. The authors propose that binding of receptor ligands might promote the correct folding of newly synthesized receptors, decreasing the possibility of degradation and ultimately leading to an increase in the steady-state level of functional receptors at the cell surface. So, these 'pharmacological chaperones' might not just be potentially useful in diseases caused by ER retention of mutant proteins, such as NDI, but also represent a novel mechanism by which receptor agonists and antagonists might mediate changes in receptor density and cell responsiveness to drugs.
Peter Kirkpatrick
References
Petäjä-Repo, U. E. et al. Ligands act as pharmacological chaperones and increase the efficiency of opioid receptor maturation. EMBO J.21, 1628–1637 (2002) | PubMed |
Morello, J.-P. et al. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J. Clin. Invest.105, 887–895 (2000) | PubMed |
opioid receptor