ARRB2
Beta-arrestin-2 (Arrestin beta-2) (Non-visual arrestin-3) [ARB2] [ARR2]
PublicationsПравить
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which irreversibly inactivates dopamine (DA) receptors, causes pronounced age-dependent behavioral effects in rats. For example, EEDQ either augments or does not affect the DA agonist-induced locomotor activity of preweanling rats while attenuating the locomotion of adolescent and adult rats. The twofold purpose of this study was to determine whether EEDQ would: (a) potentiate or attenuate the cocaine-induced locomotor activity of preweanling, adolescent, and adult rats; and (b) alter the sensitivity of surviving D2 receptors. Rats were treated with vehicle or EEDQ (2.5 or 7.5 mg/kg) on postnatal day (PD) 17, PD 39, and PD 84. In the behavioral experiments, saline- or cocaine-induced locomotion was assessed 24 hr later. In the biochemical experiments, dorsal striatal samples were taken 24 hr after vehicle or EEDQ treatment and later assayed for NPA-stimulated GTPγS receptor binding, G protein-coupled receptor kinase 6 (GRK6), and β-arrestin-2 (ARRB2). GTPγS binding is a direct measure of ligand-induced G protein activation, while GRK6 and ARRB2 modulate the internalization and desensitization of D2 receptors. Results showed that EEDQ potentiated the locomotor activity of preweanling rats, while attenuating the locomotion of older rats. NPA-stimulated GTPγS binding was elevated in EEDQ-treated preweanling rats, relative to adults, indicating enhanced functional coupling between the G protein and receptor. EEDQ also reduced ARRB2 levels in all age groups, which is indicative of increased D2 receptor sensitivity. In sum, the present results support the hypothesis that D2 receptor supersensitivity is a critical factor mediating the locomotor potentiating effects of EEDQ in cocaine-treated preweanling rats.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- Cocaine
- Corpus Striatum
- Dopamine D2 Receptor Antagonists
- Locomotion
- Male
- Quinolines
- Rats, Sprague-Dawley
- Receptors, Dopamine D2
Keywords
- G protein-coupled receptor kinase 6 (GRK6)
- GTPγS receptor binding
- N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)
- ontogeny
- β-arrestin-2 (ARRB2)
During the past decade, it has become increasingly clear that consistent changes in the levels of expression of a small cohort of genes accompany the aging of mammalian tissues. In many cases, these changes have been shown to generate features that are characteristic of the senescent phenotype. Previously, a small pilot study indicated that some of these changes might be reversed in rat liver, if the liver cells became malignant and were proliferating. The present study has tested the hypothesis that inducing proliferation in old rat liver can reset the levels of expression of these age-related genes to that observed in young tissue. A microarray approach was used to identify genes that exhibited the greatest changes in their expression during aging. The levels of expression of these markers were then examined in transcriptomes of both proliferating hepatomas from old animals and old rat liver lobes that had regenerated after partial hepatectomy but were again quiescent. We have found evidence that over 20 % of the aging-related genes had their levels of expression reset to young levels by stimulating proliferation, even in cells that had undergone a limited number of cell cycles and then become quiescent again. Moreover, our network analysis indicated alterations in MAPK/ERK and Jun-N-terminal kinase pathways and the potential important role of PAX3, VCAN, ARRB2, NR1H2, and ITGA5 that may provide insights into mechanisms involved in longevity and regeneration that are distinct from cancer.
MeSH Terms
- Aging
- Animals
- Carcinoma, Hepatocellular
- Cell Cycle
- Cell Proliferation
- Gene Expression Regulation, Neoplastic
- Genes, Neoplasm
- Hepatectomy
- Hepatocytes
- Liver
- Liver Neoplasms, Experimental
- Liver Regeneration
- Longevity
- Male
- Pilot Projects
- RNA, Neoplasm
- Rats
- Rats, Sprague-Dawley
- Reverse Transcriptase Polymerase Chain Reaction