[show abstract][hide abstract] ABSTRACT: Beta-arrestins, key regulators of receptor signaling, are highly expressed in the central nervous system, but their roles in brain physiology are largely unknown. Here we show that beta-arrestin-2 is critically involved in the formation of associative fear memory and amygdalar synaptic plasticity. In response to fear conditioning, beta-arrestin-2 translocates to amygdalar membrane where it interacts with PDE-4, a cAMP-degrading enzyme, to inhibit PKA activation. Arrb2(-/-) mice exhibit impaired conditioned fear memory and long-term potentiation at the lateral amygdalar synapses. Moreover, expression of the beta-arrestin-2 in the lateral amygdala of Arrb2(-/-) mice, but not its mutant form that is incapable of binding PDE-4, restores basal PKA activity and rescues conditioned fear memory. Taken together, our data demonstrate that the feedback regulation of amygdalar PKA activation by beta-arrestin-2 and PDE-4 complex is critical for the formation of conditioned fear memory.
Proceedings of the National Academy of Sciences 12/2009; 106(51):21918-23. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate interference of delta-opioid receptor with the Na(+),K(+)-ATPase in a simple model system, we used the Xenopus oocytes as an expression system. Our results indicate that expression of the delta-opioid receptor (DOR) results in reduction of endogenous sodium-pump activity. Stimulation of DOR by the DOR agonist [(D)-Pen(2,5)]-enkephalin (DPDPE) had no pronounced additional effect on pump activity. Qualitatively similar results were obtained in experiments with a variety of co-expressed exogenous sodium pumps. We suggest that reduced pump activity with DOR expression is brought about by an interaction of the pump with DOR. Direct interaction is also supported by co-immunoprecipitation, not only in the Xenopus oocytes but also in rat hippocampal neurons. The interaction may be responsible for altered agonist sensitivity of DOR; activation of the sodium pump led to an increase of the K(m) value for DOR activation by DPDPE from about 0.17 to 0.27muM. In conclusion, pump activity not only affects neural activity directly but our results also suggest that pump activity is affected through functional interaction with DOR that will modulate pain sensation.
Neuroscience Research 08/2009; 65(3):222-7. · 2.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Addictive drugs have been shown to severely influence many neuronal functions, which are considered as the underlying mechanisms for physiological and psychological dependences. We previously showed that in vivo LTP in rat hippocampal CA1 region is significantly reduced during withdrawal following chronic opiates treatment, and the reduced LTP can be restored by re-exposure of animals to corresponding drugs. Here, we further demonstrated that during opiates withdrawal, the re-exposure of morphine either systemically (subcutaneously) or locally (intracerebroventricularly) could restore the reduced LTP in heroin-dependent rats, but heroin could not restore the reduced LTP, in morphine-dependent rats, indicating differential modulations of hippocampal functions by those two opiates. In contrast, DAMGO, a mu-opioid receptor (MOR) agonist, could restore the reduced LTP, and CTOP, a MOR antagonist, could block the restoration in rats dependent on both opiates, showing that MOR is functional under such conditions. However, the upregulation of hippocampal PKA activity during morphine withdrawal could be suppressed by re-exposure of morphine but not that of heroin, suggesting a likely underlying mechanism of the differential modulation of LTP by two opiates. Taken together, our study clearly demonstrates that chronic abuse of opiates inevitably leads to severe alteration of hippocampal LTP, and reveals the interesting differences between morphine and heroin in their effects on the differential modulation of hippocampal synaptic plasticity.
[show abstract][hide abstract] ABSTRACT: Amyloid plaque is the hallmark and primary cause of Alzheimer disease. Mutations of presenilin-1, the gamma-secretase catalytic subunit, can affect amyloid-beta (Abeta) production and Alzheimer disease pathogenesis. However, it is largely unknown whether and how gamma-secretase activity and amyloid plaque formation are regulated by environmental factors such as stress, which is mediated by receptors including beta(2)-adrenergic receptor (beta(2)-AR). Here we report that activation of beta(2)-AR enhanced gamma-secretase activity and thus Abeta production. This enhancement involved the association of beta(2)-AR with presenilin-1 and required agonist-induced endocytosis of beta(2)-AR and subsequent trafficking of gamma-secretase to late endosomes and lysosomes, where Abeta production was elevated. Similar effects were observed after activation of delta-opioid receptor. Furthermore, chronic treatment with beta(2)-AR agonists increased cerebral amyloid plaques in an Alzheimer disease mouse model. Thus, beta(2)-AR activation can stimulate gamma-secretase activity and amyloid plaque formation, which suggests that abnormal activation of beta(2)-AR might contribute to Abeta accumulation in Alzheimer disease pathogenesis.
Nature Medicine 01/2007; 12(12):1390-6. · 22.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chromatin modification is considered to be a fundamental mechanism of regulating gene expression to generate coordinated responses to environmental changes, however, whether it could be directly regulated by signals mediated by G protein-coupled receptors (GPCRs), the largest surface receptor family, is not known. Here, we show that stimulation of delta-opioid receptor, a member of the GPCR family, induces nuclear translocation of beta-arrestin 1 (betaarr1), which was previously known as a cytosolic regulator and scaffold of GPCR signaling. In response to receptor activation, betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300, resulting in enhanced local histone H4 acetylation and transcription of these genes. Our results reveal a novel function of betaarr1 as a cytoplasm-nucleus messenger in GPCR signaling and elucidate an epigenetic mechanism for direct GPCR signaling from cell membrane to the nucleus through signal-dependent histone modification.
[show abstract][hide abstract] ABSTRACT: Amyloid plaque is the hallmark and primary cause of Alzheimer disease. Mutations of presenilin-1, the c-secretase catalytic subunit, can affect amyloid-b (Ab) production and Alzheimer disease pathogenesis. However, it is largely unknown whether and how c-secretase activity and amyloid plaque formation are regulated by environmental factors such as stress, which is mediated by receptors including b 2 -adrenergic receptor (b 2 -AR). Here we report that activation of b 2 -AR enhanced c-secretase activity and thus Ab production. This enhancement involved the association of b 2 -AR with presenilin-1 and required agonist-induced endocytosis of b 2 -AR and subsequent trafficking of c-secretase to late endosomes and lysosomes, where Ab production was elevated. Similar effects were observed after activation of d-opioid receptor. Furthermore, chronic treatment with b 2 -AR agonists increased cerebral amyloid plaques in an Alzheimer disease mouse model. Thus, b 2 -AR activation can stimulate c-secretase activity and amyloid plaque formation, which suggests that abnormal activation of b 2 -AR might contribute to Ab accumulation in Alzheimer disease pathogenesis. Alzheimer disease is the most common neurodegenerative disorder of the central nervous system. Amyloid plaques, which are largely com-posed of amyloid-b (Ab), are a major characteristic of Alzheimer disease neuropathology and considered to be the primary cause of the disease 1 . Diffusible oligomeric Ab is neurotoxic and potentially related to the disease 2 . Ab is generated from Ab precursor protein (APP) via sequential cleavages by b-and g-secretases 3 . The g-secretase is pivotal, because it determines the ratio of two main Ab species (Ab 40 and Ab 42) 4 , and mutations in its catalytic subunit presenilin-1 (PS1) account for most cases of familial Alzheimer disease (FAD) 5 . Because FAD accounts for fewer than 10% of cases of Alzheimer disease and sporadic Alzheimer disease accounts for most cases 6 , it is important to investigate how environmental influences have an impact on and con-tribute to the pathogenesis of the disease. Ab production in cell cultures can be reduced by activation of intracellular signaling pathways 7,8 or by activation of the muscarinic acetylcholine receptor or estrogen recep-tor 9,10 . Further, Ab levels and amyloid plaque formation can be reduced by environmental enrichment or somatostatin 11,12 . Therefore, it is of interest to know whether and how environmental factors can enhance g-secretase activity, amyloid plaque formation or both. Environmental factors such as stress activate receptors including b-adrenergic receptors (b-ARs) and d-opioid receptor (DOR) 13–15 . Once activated, these receptors couple to heterotrimeric guanine nucleotide–binding proteins (G proteins) and modulate the levels of intracellular second messengers, such as cyclic AMP (cAMP) 16,17 . The activated receptor also undergoes clathrin-mediated endocytosis, which is crucial for receptor desensitization and signal transduction 18,19 . These receptors, especially b 2 -AR, are well studied, typical G protein– coupled receptors (GPCRs) 19–21 and are expressed in hippocampus and cortex 22 , the main brain regions involved in Alzheimer disease 2 . So it is intriguing to examine whether some important GPCRs, like b 2 -AR, can enhance Ab production. In this study, we found that activation of b 2 -AR enhances g-secretase activity, resulting in increased Ab production. Activation of DOR induced similar effects. Furthermore, in vivo experiments with an Alzheimer disease mouse model (APPswe/ PS1DE9 double-transgenic mouse) showed that cerebral amyloid plaque formation was increased after chronic treatment with the b 2 -AR agonists isoproterenol or clenbuterol. In contrast, amyloid plaque formation was reduced after chronic treatment with a b 2 -AR antago-nist, ICI 118,551. Thus, these findings provide direct evidence that g-secretase activity and amyloid plaque formation can be enhanced by b 2 -AR–mediated extracellular signals, implying that b 2 -AR antagonists could be potential drugs for the treatment of Alzheimer disease.
[show abstract][hide abstract] ABSTRACT: Synaptic plasticity and neurogenesis in the brain are affected by environmental stimuli. The present study was designed to investigate the effects of social environments on learning and memory, neurogenesis, and neuroplasticity. Twenty-two-day-old rats were housed in isolation or in groups for 4 or 8 weeks and injected intraperitoneally with bromodeoxyuridine to detect proliferation among progenitor cells. The animals were also tested for learning in a water maze and for hippocampal CA1 long-term potentiation in vivo and in vitro. The results show that the number of newborn neurons in the dentate gyrus and the learning in a water maze decreased significantly in rats reared in isolation for 4 or 8 weeks, as compared with grouped controls. Induction of long-term potentiation in the CA1 area of rat hippocampus in vivo and in vitro was also significantly reduced by isolation. Furthermore, the effects of isolation rearing on spatial learning, hippocampal neurogenesis, and long-term potentiation could be reversed by subsequent group rearing. These findings demonstrated that social environments can modify neurogenesis and synaptic plasticity in adult hippocampal regions, which is associated with alterations in spatial learning and memory.