Bestatin, an Aminopeptidase B Inhibitor, Selectively Reduces Alcohol Intake in Rats

Szczepańska, Renata; Grupp, Larry A.

doi:10.1111/j.1530-0277.1993.tb00790.x

Cited by 12 publications

(2 citation statements)

References 17 publications

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“…2004). Moreover, an inhibitor of AP‐B, bestatin, reduces alcohol intake in rats (Szczepanska and Grupp 1993). With respect to cardiovascular regulation, administration of bestatin to brains of rats resulted in elevated blood pressure and heart rate (Chan et al.…”

Section: Discussionmentioning

confidence: 99%

Secretory vesicle aminopeptidase B related to neuropeptide processing: molecular identification and subcellular localization to enkephalin‐ and NPY‐containing chromaffin granules

Hwang

O’Neill

Bark

et al. 2006

Journal of Neurochemistry

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Biosynthesis of peptide hormones and neurotransmittters involves proteolysis of proprotein precursors by secretory vesicle cathepsin L. Cathepsin L generates peptide intermediates with basic residues at their NH 2 -termini, indicating that Arg/Lys aminopeptidase is needed to generate the smaller biologically active peptide. Therefore, this study identified the Arg/Lys aminopeptidase that is present in secretory vesicles of adrenal medulla and neuroendocrine tissues, achieved by molecular cloning and localization in 'model' neuropeptidecontaining secretory vesicles (bovine). Molecular cloning of the bovine aminopeptidase B (AP-B) cDNA defined its primary sequence that allowed selection of antisera for immunolocalization studies. AP-B was present in secretory vesicles that contain cathepsin L with the neuropeptides enkephalin and neuropeptide Y. The AP-B in several neuroendocrine tissues was detected by western blots. Recombinant bovine AP-B showed preference for Arg-methylcoumarinamide substrate. AP-B was inhibited by arphamenine, an inhibitor of aminopeptidases. Bovine AP-B showed similar activities for Arg-(Met)enkephalin (ME) and Lys-ME neuropeptide substrates to generate ME, while rat AP-B preferred Arg-ME. Furthermore, AP-B possesses an acidic pH optimum of 5.5-6.5 that is similar to the internal pH of secretory vesicles. The significant finding of the secretory vesicle localization of AP-B with neuropeptides and cathepsin L suggests a role for this exopeptidase in the biosynthesis of neuropeptides. Neuropeptides play significant roles for mediating cell-cell communication in neuroendocrine systems as peptide neurotransmitters and hormones. These biologically active peptides are synthesized by proteolytic processing of proprotein precursors in the regulated secretory pathway of neurons and endocrine cells. Processing occurs primarily within secretory vesicles as the major subcellular site for neuropeptide biosynthesis. Mature neuropeptides are stored in such secretory vesicles for controlled secretion.The precursors of endogenous enkephalin and related opioid neuropeptides have been utilized for elucidating protease pathways that participate in the biosynthesis of active neuropeptides. Examination of the major proenkephalin-cleaving activity in enkephalin-containing secretory vesicles purified from adrenal medullary chromaffin cells revealed that the cysteine protease cathepsin L participates in the production of (Met)enkephalin (ME; Yasothornsrikul et al.

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Section: Discussionmentioning

confidence: 99%

Secretory vesicle aminopeptidase B related to neuropeptide processing: molecular identification and subcellular localization to enkephalin‐ and NPY‐containing chromaffin granules

Hwang

O’Neill

Bark

et al. 2006

Journal of Neurochemistry

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“…For the APN assay, the substrate solution was made of 100 μM Leu-β-NA (final concentration) in 50 mM Tris-HCl, pH 7.4, in the presence or absence of 500 nM bestatin. APN activity was 74.3% inhibited by bestatin, an inhibitor of several aminopeptidase activities, such as aminopeptidases B and M (Szczepanska and Grupp 1993). Thus, all determinations were performed in the absence of this inhibitor.…”

Section: Fluorometric Assay Of Nep and Apn Activitiesmentioning

confidence: 99%

Activity and Expression of Enkephalinase and Aminopeptidase N in Regions of the Mesocorticolimbic System are Selectively Modified by Acute Ethanol Administration

et al. 2011

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Opioid peptides play a key role in ethanol reinforcement and alcohol drinking behavior. However, regulation of opioid levels by peptidase-degrading activities in ethanol's actions in brain is still unclear. The aim of this work was to study the acute effects of ethanol (2.5 g/kg) on enkephalinase (NEP) and aminopeptidase N (APN) activities and expression in regions of the mesocorticolimbic system, as well as on corticosterone levels in serum for up to 24 h after administration. Enzymatic activities were measured by fluorometric assays, mRNA's expression by reverse transcriptase polymerase chain reaction (RT-PCR) and corticosterone levels by radioimmunoassay. Acute ethanol administration modified peptidase activity and expression with different kinetics. Ethanol induced a transitory increase and decrease in NEP and APN activities in the frontal cortex (FC) and ventral tegmental area (VTA), whereas only increases in these activities were observed in the nucleus accumbens (NAcc). Ethanol induced an increase in NEP mRNA in the FC and decreases in APN mRNA in the FC and NAcc. In contrast, ethanol produced biphasic effects on both enzymes expression in the VTA. Corticosterone levels were not changed by ethanol. Our results suggest that NEP and APN could play a main role in ethanol reinforcement through regulation of opioid levels in mesolimbic areas.

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Acute Ethanol Administration Differentially Alters Enkephalinase and Aminopeptidase N Activity and mRNA Levels in Regions of the Nigrostriatal Pathway

et al. 2012

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Opioid peptides play a key role in ethanol reinforcement and may also represent important determinants in brain sensitivity to ethanol through modulation of nigrostriatal dopaminergic activity. Regulation of opioid levels by peptidase-degrading enzymes could be relevant in ethanol's actions. The aim of this work was to study the acute ethanol (2.5 g/kg) effects on the activity and mRNA expression of enkephalinase (NEP) and aminopeptidase N (APN) in the rat substantia nigra (SN) and the anterior-medial (amCP) and medial-posterior (mpCP) regions of the caudate-putamen (CP). Enzymatic activities were measured by fluorometric assays and mRNA expression by reverse transcriptase polymerase chain reaction. Acute ethanol administration differentially altered peptidase activities and mRNA expression with different kinetics. Ethanol increased and decreased NEP mRNA levels in the SN and amCP, respectively, but produced biphasic effects in the mpCP. APN mRNA levels were increased by ethanol in all brain regions. Ethanol induced a transient and long-lasting increase in NEP (mpCP) and APN (amCP) activities, respectively. Peptidase activities were not changed by ethanol in the SN. Our results indicate that striatal NEP and APN are important ethanol targets. Ethanol-induced changes in these neuropeptidases in the CP could contribute to the mechanisms involved in brain sensitivity to ethanol.

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Bestatin, an Aminopeptidase B Inhibitor, Selectively Reduces Alcohol Intake in Rats

Cited by 12 publications

References 17 publications

Secretory vesicle aminopeptidase B related to neuropeptide processing: molecular identification and subcellular localization to enkephalin‐ and NPY‐containing chromaffin granules

Secretory vesicle aminopeptidase B related to neuropeptide processing: molecular identification and subcellular localization to enkephalin‐ and NPY‐containing chromaffin granules

Activity and Expression of Enkephalinase and Aminopeptidase N in Regions of the Mesocorticolimbic System are Selectively Modified by Acute Ethanol Administration

Acute Ethanol Administration Differentially Alters Enkephalinase and Aminopeptidase N Activity and mRNA Levels in Regions of the Nigrostriatal Pathway

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