Disease relevance of PENK

• In contrast, increased synthesis of proenkephalin in response to phorbol esters was not affected by pertussis toxin treatment [1].
• Recombinant PE was obtained by high level expression in Escherichia coli, with the pET3c expression vector; PE was then purified from E. coli by DEAE-Sepharose chromatography, preparative gel electrophoresis, and reverse-phase HPLC [2].

High impact information on PENK

• The amino acid sequence of amidorphin corresponds to the sequence 104-129 of bovine proenkephalin A [3].
• One pathway, dependent on calcium and not mimicked by increased intracellular cyclic AMP, leads to exocytotic hormone release; the other, probably via a calcium-dependent increase in intracellular cyclic AMP, leads to a compensatory increase in intracellular enkephalin through activation of transcription of the proenkephalin structural gene [4].
• Accordingly, we have investigated the effect of nicotinic receptor stimulation on Met-enkephalin peptide biosynthesis and expression of proenkephalin messenger RNA in primary cultures of bovine chromaffin cells [4].
• Although there is evidence that the proenkephalin is identical in the brain and the adrenal medulla, similar intermediates have not been isolated from brain [5].
• Several intermediates in the processing of proenkephalin, containing from one to four copies of [Met] enkephalin, have been purified from the adrenal medulla [5].

Chemical compound and disease context of PENK

• Combinations of IBMX plus nicotine, VIP, or histamine also synergistically enhanced proenkephalin synthesis, with no further elevation when the cells were also pretreated with pertussis toxin [1].
• The action of forskolin, a direct activator of adenylate cyclase, on proenkephalin synthesis was similarly potentiated by pertussis toxin or IBMX, presumably reflecting the abilities of both the toxin and this phosphodiesterase inhibitor to enhance the cyclic AMP response to forskolin [1].
• Pertussis toxin pretreatment also increased proenkephalin synthesis in chromaffin cells exposed to vasoactive intestinal peptide (VIP) and 3-isobutyl-1-methylxanthine (IBMX) [1].
• Forskolin (an adenyl cyclase activator) and isobutyl methyl xanthine (a phosphodiesterase inhibitor) increased both ME secretion and proENK mRNA levels; pertussis toxin synergistically increased the secretion of ME with these cyclic AMP-elevating agents but had only an additive effect with these agents on the level of proENK mRNA [6].

Biological context of PENK

• Proenkephalin A gene expression in bovine adrenal chromaffin cells is regulated by changes in electrical activity [7].
• Evidence for the phosphorylation of a proenkephalin-derived peptide, peptide B [8].
• A third mode of action by protein kinase C to modulate proenkephalin gene expression is by interaction with the phosphatidylinositol second messenger system [9].
• There is increasing evidence that the opioid peptide precursor, proenkephalin A, and its products undergo extensive post-translational modification, in addition to the cleavage at dibasic amino acid sites [10].
• Stimulation of phosphoinositide hydrolysis and proenkephalin mRNA by histaminic H1-receptor activation was inhibited by low concentrations of PMA [9].

Anatomical context of PENK

• The processing of the precursor protein proenkephalin was studied in two different bovine tissues, the hypothalamus and adrenal medulla [11].
• Considerable differences were found for the abundance of proenkephalin A mRNA in the various tissues: from 0.023% in the adrenal medulla to 0.00002% in the adenohypophysis [12].
• This antiserum enabled an investigation of the stability and molecular properties of intermediates in the processing of proenkephalin in bovine adrenal medullary chromaffin granules [13].
• A putative processing enzyme for proenkephalin, with activity directed toward basic residues, was purified over 2000-fold from washed bovine adrenal medullary chromaffin granule membranes [14].
• These results show that an NH2 terminally extended Met-enkephalin Arg6-Gly7-Leu8 variant was N-glycosylated, and hence indicate that the precursor polypeptide proenkephalin A can be glycosylated during translation in the rough endoplasmic reticulum [15].

Associations of PENK with chemical compounds

• The vasopressin-immunoreactive cells were never stained with either the proenkephalin or the [Met]enkephalin antisera [16].
• Cysteine proteases have been implicated in the processing of proenkephalin and other neuropeptide precursors [17].
• Low concentrations (0.5-100 pM) of dexamethasone increased the cell contents of proenkephalin mRNA and enkephalin-containing peptides [18].
• Aldosterone, progesterone, testosterone, or estradiol (1 microM) failed to change proenkephalin mRNA [18].
• The precise localization of proenkephalin and [Met]enkephalin immunoreactivities was compared to the distribution of oxytocin and vasopressin in serial 5-micron sections through the magnocellular nuclei [16].

Regulatory relationships of PENK

• A calcium-initiated signaling pathway propagated through calcineurin and cAMP response element-binding protein activates proenkephalin gene transcription after depolarization [19].
• Pretreatment of the cells with nicotine, histamine, or vasoactive intestinal peptide to enhance the rate of proenkephalin synthesis failed to alter the time course of processing and had minimal effects on the distribution of products formed [20].
• Insulin-like growth factor I enhances proenkephalin synthesis and dopamine beta-hydroxylase activity in adrenal chromaffin cells [21].

Other interactions of PENK

• Coordinate and differential regulation of proenkephalin A and PNMT mRNA expression in cultured bovine adrenal chromaffin cells: responses to secretory stimuli [22].
• In contrast, the 70-kDa aspartic proteinase cleaved POMC most readily, with cleavage of proenkephalin and some processing of pro-NPY [23].
• Proenkephalin, [Met]enkephalin, and oxytocin immunoreactivities are colocalized in bovine hypothalamic magnocellular neurons [16].
• This study demonstrates that "protease nexin 2 (PN2)," the secreted form of the kunitz protease inhibitor (KPI) of the amyloid precursor protein (APP), potently inhibited the proenkephalin processing enzyme known as prohormone thiol protease (PTP), with a Ki,app of 400 nM [24].
• The other opioid peptides were [Met]-enkephalyl-Arg6-Phe7 and [Met]-enkephalyl-Arg6-Gly7-Leu8 from proenkephalin; alpha-neoendorphin, beta-neoendorphin, dynorphin A(1-8), dynorphin A(1-17), and dynorphin B from prodynorphin; and [Leu]-enkephalin, which can be derived from either precursor [25].

Analytical, diagnostic and therapeutic context of PENK

• Molecular cloning establishes proenkephalin as precursor of enkephalin-containing peptides [26].
• In all tissues, a single hybridizable species of 1400 bases in size was found by Northern blot analysis using as a probe a single-stranded (ss) cDNA complementary to bovine proenkephalin A mRNA [12].
• Amino acid composition analysis and gas-phase sequence analysis revealed identity of this peptide with residues 8-26 of the proenkephalin-derived opioid peptide amidorphin, which we have recently isolated from bovine adrenal medulla [27].
• An antiserum was generated against a synthetic peptide corresponding to amino acids 95-117 of bovine proenkephalin, and a sensitive radioimmunoassay was developed [28].
• Analysis of hypotonic lysates by two-dimensional gel-electrophoresis showed that proenkephalin intermediates exhibit significant microheterogeneity [13].

References