Proenkephalin

Fig. 1. Schematic drawing of precursors for selected brain oligopeptides. Shaded areas represent the location of sequences of active peptide products which are normally cleaved by trypsin-like enzymes acting on double-basic amino acid residues. Precursors are not necessarily drawn to scale, (a) CRF precursor (b) proopiomelanocortin (POMC) (c) P-protachykinin (d) proenkephalin A (e) CGRP precursor (f) preprodynorphin, ie, preproenkephalin B. Terms are...

Delta receptors are relatively selective for two related penta-peptides, methionine enkephalin and leucine enkephalin (met- and leu-enkephalin), which were isolated from porcine brain (Hughes 1975). Both met- and leu-enkephalin inhibit electrically induced contractions of guinea pig ileum, an effect that mimics those effects seen with opioid drugs, and is naloxone reversible. The enkephalins are processed posttranslational ly from proenkephalin, and secreted from central and peripheral neurons and endocrine cells in the adrenal medulla. 

Przewlocka B., Lason W. Adaptive changes in the proenkephalin and D2 dopamine receptor mRNA expression after chronic cocaine in the nucleus accumbens and striatum of the rat. Neuropsychopharmacology. 5 464, 1995. 

The number of neural genes known to contain CREs is growing as more and more genes are cloned. Prominent examples are tyrosine hydroxylase, c-fos, proenkephalin, prodynorphin, somatostatin and vasoactive intestinal polypeptide (VIP). Expression of these genes has been... 

Endogenous opioids are peptides that are cleaved from the precursors proenkephalin, pro-opiomelanocortin, and prodynorphin. All contain the amino acid sequence of the pentapeptides [Met]- or [Leuj-enkephalin (A). The effects of the opioids can be abolished by antagonists (e.g., naloxone A), with the exception of buprenorphine. 

Bilkei-Gorzo A, Schuetz B, Zimmer A (2001) Influence of the genetic background on the reactivity ofpre-proenkephaline knockout mice in models of anxiety. Soc Neurosci Abstr 955.9... 

Goss, J.R., Mata, M., Goins, W.F., Wu, H.H., Glorioso, J.C., Fink, D.J. Antinociceptive effect of a genomic herpes simplex virus-based vector expressing human proenkephalin in rat dorsal root ganglion, Gene Ther. 2001, 8, 551-556. 

Both Met-enkephalin and Leu-enkephalin have their own pro- and prepro forms.29 Bovine preproenkephalin A is a 268-residue protein containing a 20-residue signal sequence and four sequences of Met-enkephalin and one of Leu-enkephalin, each flanked by pairs of basic residues. There are also Met-enkephalin-Arg-Gly-Leu (YGGFMRGL) and Met-enkephalin-Arg-Phe sequences. Not all of these are cut out cleanly, and other peptides such as Met-enkephalin-Arg-Arg-Val-NH2 are also found in brain. Proenkephalin B contains three copies of Leu-enkephalin contained within longer peptides. One of these, P-dynorphin (Table 30-4), is also a potent opioid compound. The enkephalins are thought to act as neurotransmitters, which are rapidly degraded after their release by two or three membrane-bound... 

Opiates act on a variety of receptors. The three most important subtypes are the mu, delta, and kappa opiate receptors (Fig. 13—25). The brain makes its own endogenous opiate-like substances, sometimes referred to as the brain s own morphine. They are peptides derived from precursor proteins called pro-opiomelanocortin (POMC), proenkephalin, and prodynorphin. Parts of these precursor proteins are cleaved off to form endorphins or enkephalins, stored in opiate neurons, and presumably released during neurotransmission to mediate endogenous opiate-like actions (Fig. 13-25). However, the precise number and function of endogenous opiates and their receptors and their role in pain relief and other central nervous system (CNS) actions remain largely unknown. 

Note Three distinct families of peptides have been identified the enkephalins, the endorphins, and the dynorphins. Each family is derived from a distinct precursor polypeptide and has a characteristic anatomical distribution. These precursors are now designated as proenkephalin (also proenkephalin A), proopiomelanocortin (POMP), and prodynorphin (also proenkephalin). 

Le, Y., Gagneten, S., Larson, T., Santha, E., Dobi, A., v. Agoston, D., and Sauer, B. (2003) Far-upstream elements are dispensable for tissue-specific proenkephalin expression using a Cre-mediated knock-in strategy. 

The endogenous opioid peptides have a range of affinities for the different types of opioid receptor. Some met-enkephalin derivatives, for example, show affinity for mu and delta receptors, whereas other peptides, derived from proenkephalin, show a preference for the delta sites. All peptides from prodynorphin act predominantly on kappa sites, while beta-endorphin behaves like the enkephalins and shows selectivity for the mu and delta sites. 

Seizinger, B. R., Grimm, C., Hollt, V., and Herz, A. (1984). Evidence for a selective processing of proenkephalin B into different opioid peptide forms in particular regions of rat brain and pituitary. 

Today, we know that there are three types of opioid receptors—mu, delta, and kappa receptors [see review 3]. Proenkephalin contains six copies of Met-enkephalins and one copy of Leu-enkephalin. Enkephalins, especially Leu-enkephalin, are believed to be selective to delta receptors. Opiomelano-cortin contains (3-endorphin that has the Met-enkephalin at its amino terminus. (3-Endorphin is a nonselective ligand for mu and delta receptors. 

The relatively large number of opioid peptides isolated in recent years is a reflection of the complexity of the endogenous opioid system. The major opioid peptides are cleavage products of three distinct proteins, which are the primary products of three genes. These precursor proteins are proenkephalin... 

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