Descoberto mecanismo celular que protege contra doença

segunda-feira, fevereiro 22, 2010

Cellular Mechanism That Protects Against Disease Discovered

ScienceDaily (Feb. 21, 2010) — Researchers at Oregon Health & Science University have discovered a new mechanism within human cells that constantly protects us against disease. P. Michael Conn, Ph.D., a researcher at the OHSU Oregon National Primate Research Center directed the work. The findings are reported in the Feb. 15 issue of the journal Proceedings of the National Academy of Sciences.

"Cells communicate with each other by releasing chemical signals, like hormones," explained Conn. "These chemical signals are detected and received by structures called 'receptors' which reside in the outer membranes of other cells. Sometimes environmental toxins or radiation can cause mutations in these receptors. When this happens, these mutant receptors make errors -- they may activate unexpectedly or fail to activate at all -- and this behavior results in disease."
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Salt bridge integrates GPCR activation with protein trafficking

Jo Ann Janovick a and P. Michael Conn a,b,1

-Author Affiliations

aDivisions of Reproductive Sciences and Neuroscience, Oregon National Primate Research Center, and

bDepartments of Physiology and Pharmacology, Cell and Developmental Biology and Obstetrics and Gynecology, Oregon Health and Science University, Beaverton, OR 97006

Edited* by Susan E. Leeman, Boston University School of Medicine, Boston, MA, and approved January 26, 2010 (received for review December 9, 2009)


G protein–coupled receptors (GPCRs) play central roles in almost all physiological functions; mutations in GPCRs are responsible for more than 30 disorders. There is a great deal of information about GPCR structure but little information that directly relates structure to protein trafficking or to activation. The gonadotropin releasing hormone receptor, because of its small size among GPCRs, is amenable to preparation of mutants and was used in this study to establish the relation among a salt bridge, protein trafficking, and receptor activation. This bridge, between residues E90 [located in transmembrane segment (TM) 2] and K121 (TM3), is associated with correct trafficking to the plasma membrane. Agonists, but not antagonists, interact with residue K121, and destabilize the TM2–TM3 association of the receptor in the plasma membrane. The hGnRHR mutant E90K has a broken salt bridge, which also destabilizes the TM2–TM3 association and is typically retained in the endoplasmic reticulum. We show that this mutant, if rescued to the plasma membrane by either of two different means, has constitutive activity and shows modified ligand specificity, revealing a role for the salt bridge in receptor activation, ligand specificity, trafficking, and structure. The data indicate that destabilizing the TM2–TM3 relation for receptor activation, while requiring an intact salt bridge for correct trafficking, provides a mechanism that protects the cell from plasma membrane expression of constitutive activity.

constitutive activity   hormone action   receptor    G-protein coupled receptor   receptor trafficking


1To whom correspondence should be addressed. E-mail:

Author contributions: J.A.J. and P.M.C. designed research; performed research; analyzed data; and wrote the paper.

The authors declare no conflict of interest.

↵*This Direct Submission article had a prearranged editor.

Conn and his colleague Jody Janovick, B.S., R.Ph. a senior research associate discovered that when certain receptors, called G-protein coupled receptors, become "constitutively activated" by mutation, they are naturally detected by a mechanism in the body and targeted for destruction so they cannot cause disease.


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