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ARF6: a newly appreciated player in G protein-coupled receptor desensitization
Mary Hunzicker-Dunn1, Vsevolod V Gurevich, James E Casanova
1Department of Cell and Molecular Biology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA. mhd@northwestern.edu
Abstract:
The luteinizing hormone/choriogonadotropin hormone receptor (LH/CG R) signals to regulate ovulation, corpus luteum formation, and fetal survival during pregnancy. Agonist binding to the LH/CG R is poorly reversible, emphasizing the importance of a cellular mechanism to temper signaling by a potentially persistently active receptor. Like other G protein-coupled receptors (GPCRs), signaling by this receptor is modulated by its binding of an arrestin. We have identified ADP ribosylation factor 6 (ARF6) as a protein whose activation state is regulated by the LH/CG R and which functions to regulate the availability of plasma membrane-docked arrestin 2 to this receptor. We hypothesize that ARF6 might also serve GPCRs other than the LH/CG R to regulate the availability of arrestin 2 for receptor desensitization.
Insights
The luteinizing hormone/choriogonadotropin hormone receptor (LH/CG R) signaling is regulated by arrestin availability, controlled by ADP ribosylation factor 6 (ARF6). ARF6 influences arrestin 2 docking to the plasma membrane for receptor desensitization.
Area of Science:
- Endocrinology
- Molecular Cell Biology
- G protein-coupled receptor (GPCR) signaling
Background:
- The luteinizing hormone/choriogonadotropin hormone receptor (LH/CG R) plays crucial roles in reproduction, including ovulation and pregnancy maintenance.
- Persistent agonist binding to the LH/CG R necessitates cellular mechanisms for signal termination.
- G protein-coupled receptor (GPCR) signaling, including that of the LH/CG R, is modulated by arrestin proteins.
Purpose of the Study:
- To investigate the role of ADP ribosylation factor 6 (ARF6) in regulating LH/CG R signaling.
- To determine how ARF6 influences the availability of arrestin 2 for LH/CG R desensitization.
Main Methods:
- Identification of ARF6 as a regulator of LH/CG R signaling.
- Analysis of ARF6's effect on plasma membrane-localized arrestin 2.
Main Results:
- ARF6 activation state is regulated by the LH/CG R.
- ARF6 controls the availability of plasma membrane-docked arrestin 2 to the LH/CG R.
- This interaction is crucial for receptor desensitization.
Conclusions:
- ARF6 is a key regulator of LH/CG R signaling by modulating arrestin 2 availability.
- The findings suggest a novel mechanism for GPCR desensitization involving ARF6.
- ARF6 may play a broader role in regulating other GPCRs via arrestin availability.