Galphao/i-stimulated proteosomal degradation of RGS20: a mechanism for temporal integration of Gs and Gi pathways.
The G(s) and G(i) pathways interact to control the levels of intracellular cAMP. Although coincident signaling through G(s) and G(i)-coupled receptors can attenuate G(s)-stimulated cAMP levels, it is not known if prior activation of the G(i) pathway can affect signaling by G(s)-coupled receptors. We have found that activated Galpha(o/i) interact with RGS20, a GTPase activating protein for members of the Galpha(omicron/i) family. Interaction between Galpha(o/i) and RGS20 results in decreased cellular levels of RGS20. This decrease was induced by activated Galpha(o) and Galpha(i2) but not by Galpha(q), Galpha(i1) or Galpha(i3.) The Galpha(o/i)-induced decrease in RGS20 can be blocked by proteasomal inhibitors lactacystin or MG132. Activated Galpha(o) stimulates the ubiquitination of RGS20. The serotonin-1A receptor that couples to G(o/i) reduces the levels of RGS20 and this effect is blocked by lactacystin, suggesting that G(o/i) promotes the degradation of RGS20. Expression of RGS20 attenuates the inhibition of beta-adrenergic receptor-induced cAMP levels mediated by the serotonin-1A receptor. Prior activation of the serotonin-1A receptor results in loss of the RGS20-mediated attenuation, and the loss of attenuation is blocked when lactacystin is included during the prior treatment. These observations suggest that G(o/i)-coupled receptors, by stimulating the degradation of RGS20, can regulate how subsequent activation of the G(s) and G(i) pathways controls cellular cAMP levels, thus allowing for signal integration.
Pagano
Mario
M
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, United States.
Jordan
J Dedrick
JD
Neves
Susana R
SR
Nguyen
Tracy
T
Iyengar
Ravi
R
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D020710:RGS Proteins / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
D020710:RGS Proteins; D044282:Receptor, Serotonin, 5-HT1A; D046988:Proteasome Endopeptidase Complex; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs