Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P19086 (Galphaz)
 110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two consecutive i.c.v. administrations of analgesic doses of mu-opioid receptor agonists lead to a profound desensitisation of the latter receptors; a third dose produced less than 20% of the effect obtained with the first administration. Desensitisation was still effective 24h later. Impairing the activity of Galphaz but not Galphai2 subunits prevented tolerance developing after the administration of three consecutive doses of morphine. Further, the i.c.v. injection of Galphai2 subunits potentiated morphine analgesia and abolished acute tolerance, whereas i.c.v.-administered Galphaz subunits produced a rapid and robust loss of the response to morphine. The RGSZ1 and RGSZ2 proteins selectively deactivate GalphazGTP subunits, and their knockdown increased the effects produced by the first dose of morphine. However, impairing their activity also accelerated tachyphylaxis following successive doses of morphine, and facilitated the development of acute morphine tolerance. In contrast, inhibiting the RGS9-2 proteins, which bind to GalphaoGTP and GalphaiGTP but only weakly deactivates them, preserved the effects of consecutive morphine doses and abolished the generation of acute tolerance. Therefore, desensitisation of mu-opioid receptors can be achieved by reducing the responsiveness of post-receptor elements (via the possible action of activated Galphaz subunits) and/or by depleting the pool of receptor-regulated G proteins that agonists need to propagate their effects, e.g., through the activity of RGS9-2 proteins.
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PMID:RGS-Rz and RGS9-2 proteins control mu-opioid receptor desensitisation in CNS: the role of activated Galphaz subunits. 1561 34

The regulator of G-protein signaling RGS17(Z2) is a member of the RGS-Rz subfamily of GTPase-activating proteins (GAP) that efficiently deactivate GalphazGTP subunits. We have found that in the central nervous system (CNS), the levels of RGSZ2 mRNA and protein are elevated in the hypothalamus, midbrain, and pons-medulla, and that RGSZ2 is glycosylated in synaptosomal membranes isolated from CNS tissue. In analyzing the function of RGSZ2 in the CNS, we found that when the expression of RGSZ2 was impaired, the antinociceptive response to morphine and [D-Ala2, N-MePhe4, Gly-ol5]-enkephalin (DAMGO) augmented. This potentiation involved mu-opioid receptors and increased tolerance to further doses of these agonists administered 24 h later. High doses of morphine promoted agonist desensitization even within the analgesia time-course, a phenomenon that appears to be related to the great capacity of morphine to activate Gz proteins. In contrast, the knockdown of RGSZ2 proteins did not affect the activity of delta receptor agonists, [D-Pen2,5]-enkephalin (DPDPE), and [D-Ala2] deltorphin II. In membranes from periaqueductal gray matter (PAG), both RGSZ2 and the related RGS20(Z1) co-precipitated with mu-opioid receptors. While a morphine challenge reduced the association of Gi/o/z with mu receptors, it increased their association with the RGSZ2 and RGSZ1 proteins. However, only Galphaz subunits co-precipitated with RGSZ2. Doses of morphine that produced acute tolerance maintained the association of Galpha subunits with RGSZ proteins even after the analgesic effects had ceased. These results indicate that both RGSZ1 and RGSZ2 proteins influence mu receptor signaling by sequestering Galpha subunits, therefore behaving as effector antagonists.
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PMID:The RGSZ2 protein exists in a complex with mu-opioid receptors and regulates the desensitizing capacity of Gz proteins. 1582 71