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Dexras1 inhibits adenylyl cyclase.
T E Graham1, Z Qiao, R I Dorin
1New Mexico Veterans Affairs Health Care System, Medical Service (111), Departments of Medicine and Biochemistry/Molecular Biology, University of New Mexico School of Medicine, 1501 San Pedro Blvd. SE, Albuquerque, NM 87108, USA.
Biochemical and Biophysical Research Communications
|March 17, 2004
Summary
Dexras1 activates Gi signaling pathways independently of receptors. This activation inhibits adenylyl cyclase and CREB, suggesting a role in cAMP-PKA-CREB pathway regulation.
Area of Science:
- Molecular Biology
- Cell Signaling
- Endocrinology
Background:
- Dexras1 is a Ras family G protein activated by steroid hormones.
- It acts as a receptor-independent activator of Gi/o family heterotrimeric G proteins.
- Adenylyl cyclase activity is regulated by inhibitory G alpha subunits.
Purpose of the Study:
- To investigate the effects of Dexras1 on adenylyl cyclase activity.
- To determine the signaling pathways involved in Dexras1-mediated inhibition.
- To assess Dexras1's impact on cAMP levels and CREB activation.
Main Methods:
- Expression of Dexras1 and constitutively active Gsalpha.
- Measurement of intracellular cAMP levels.
- Assessment of CREB activation.
- Use of pertussis toxin, RGS4, and dominant-interfering Gi alpha2 mutants.
Main Results:
- Dexras1 expression significantly inhibited cAMP levels.
- This inhibition was blocked by pertussis toxin and RGS4, but not by Gi alpha2 mutants.
- Dexras1 decreased forskolin-stimulated CREB activation, an effect also blocked by RGS4.
- Findings suggest activation of both G alpha and G beta gamma subunits of Gi.
Conclusions:
- Dexras1 mediates ligand-independent activation of Gi signaling.
- Dexras1 inhibits adenylyl cyclase and CREB activation via Gi pathways.
- Dexras1 may play a physiological role in regulating the cAMP-PKA-CREB pathway.