P-Dynorphin

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... 

Penicillolysin showed a high affinity toward the Pro-X ( = Gin, Lys, Leu or Arg) bonds of substance P, dynorphin A [1-13], neurotensin and chicken brain pentapeptide, and the R-R bonds in dynorphin A and neurotensin (Figure 13) [69], Preferential cleavages of bonds by the enzyme with hydrophobic amino acid residues at the Pi position were observed on the peptides used (Figure 13). The specificity of penicillolysin differs from that of other metalloprotinases. 

The endogenous ligands for the opioid receptors are peptides known as the endorphins (endogenous morphine) or opio-peptins. These include the pentapep tides methionine-enkephalin and leucine-enkephalin and a hep tapep tide and octapeptide version of methionine-enkephalin, all derived from preproenkephalin p-endorphin derived from proopiomelanocortin a-and p-dynorphin derived from prodynorphin endomorphin-1 and -2, whose precursor has not been definitively identified and orphanin FQ or nociceptin, derived from OFQ/N precursor protein. These peptides are discussed in more detail in Chapter 34. 

Biosynthesis. Three separate genes encode the opioid peptides (see Fig. 1). Enkephalin is derived from preproenkephalin A, which contains six copies of Met-enkephalin and extended peptides, and one copy of Leu-enkephalin (62—66). ( -Endorphin is one of the many products of POMC, and represents the N-terminal 31 amino acids of P-Hpotropin (67,68). Three different dynorphin peptides are derived from the third opioid gene, preproenkephalin B, or preprodynorphin (69). The dynorphin peptides include dynorphin A, dynorphin B, and a-neo-endorphin. 

At the time of the discovery of Met-enkephalin, its sequence was observed to be identical to that of residues 61—65 contained in the C-fragment of the pituitary hormone p-Hpotropin [12584-99-5] (p-LPH) (see Hormones), first isolated in 1964 (11). In 1976, the isolation of a larger peptide fragment, P-endorphin [60617-12-1] that also displayed opiate-like activity was reported (12). This peptide s 31-amino-acid sequence comprised residues 61—91 of P-LPH. Subsequentiy, another potent opioid peptide, dynorphin [72957-38-17, was isolated from pituitary (13). The first five amino acids (qv) of this 17-amino-acid peptide are identical to the Leu-enkephalin sequence (see Table 1). 

The Group III peptides come from the 256-amino acid precursor, pro-dynorphin [88402-55-5] (pro-enkephalin B). This group contains dynorphin A [80448-90-4] and B [85006-82-2] as weU as a-neoendorphin [77739-20-9] (Fig. 2), all of which can be further cleaved to form biologically active iatermediates, eg, dynorphin A g and P-neoendorphin [77739-21-0] (a-neoendorphin ) (28). The longer of these peptides are relatively basic because of the number of Lys and Arg residues. 

The opioid peptides vary in their binding affinities for the multiple opioid receptor types. Leu- and Met-enkephalin have a higher affinity for 5-receptors than for the other opioid receptor types (68), whereas the dynorphin peptides have a higher affinity for K-sites (69). P-Endorphin binds with equal affinity to both p- and 5-receptors, but binds with lower affinity to K-sites (70). The existence of a P-endorphin-selective receptor, the S-receptor, has been postulated whether this site is actually a separate P-endorphin-selective receptor or is a subtype of a classical opioid receptor is a matter of controversy (71,72). The existence of opioid receptor subtypes in general is quite controversial although there is some evidence for subtypes of p- (73), 5-(74), and K-receptors (72,75), confirmation of which may be obtained by future molecular cloning studies. 

Dynorphin may also influence nociception at the spinal level. The levels of prodynorphin mRNA and immunoreactive dynorphin increase in the chronic inflammatory arthritic model (158). Dynorphin also inhibits morphine or P-endorphin-induced analgesia in naive animals and enhances analgesia in tolerant animals, indicating that this peptide may have a regulatory role in opioid analgesia (159). This effect does not appear to be mediated by a classical opioid receptor, since des-tyrosine dynorphin, which does not bind to opioid receptors, also antagonizes morphine analgesia (160). 

Litde is known about metaboHc inactivation of ( -endorphin and the dynorphins. NEP, and to a lesser extent APN, are only weaMy active against P-endorphin (183). Enzymes are known which degrade P-endorphin in vitro under nonphysiological conditions (202) or which inactivate P-endorphin by N-acetjlation (203). Alack of specific degradative enzymes for these peptides may account for their relatively long half-life in vivo though this has not been definitively estabUshed. 

A 17 amino acid long peptide sequentially related to opioid peptides in particular dynorphin A. OFQ/N is inactive at the 5, k, and p opioid receptors, but binds to its own NOP receptor (formerly ORL-1, for opioid receptor like-1). In contrast to opioid peptides, OFQ/N has no direct analgesic properties. OFQ/N is the first example for the discovery of a novel neurotransmitter from tissue extracts by using an orphan receptor as bait. Centrally administered in rodents, OFQ/N exerts anxiolytic properties. OFQ/N agonists and antagonists... 

Three endogenous opioids have been identified enkephalins, dynorphins and beta-endorphins. These opioid peptides selectively bind to the seven transmembrane GPCRs delta (8), kappa (k), and mu (p). Although dynorphin binds predominately to the k receptor, P-endorphines and enkephalins bind to p and 8 opioid receptors. It is important to note that the analgesia induced by opioids is mediated predominately throngh the p opioid receptor. In vitro studies have shown a decrease in the immnne function and proliferation following p-endorphin administration in rodents (Ray and Cohn 1999) and that the immunosuppressive effects by P-endorphins are steroid-independent (Berkenbosch et al. 1984 Nelson et al. 2000). 

RESPONSE Right. And we have asked ourselves the question because of the issue of coexistence, not only with substance P but with neurotensin and probably dynorphin. Is this the reason these things are changing Because if they are coexisting with dopamine projections and there is some alteration in dopamine, then maybe there is an intraneuronal action that results in the peptide changes. 

Herrera-Marschitz, M. Christensson-Nylander, 1. Sharp, T. Staines, W. Reid, M. Hokfelt, T. Terenius, L. and Ungerstedt, U. Striatonigral dynorphin and substanee P pathways in the rat IL Funetional analysis. Exp Brain Res 64 193. 1986. 

Paterlini G, Portoghese P, Ferguson D. Molecular simulation of dynorphin A-(1—10) binding to extracellular loop 2 of the kappa opioid receptor. A model for receptor activation. J Med Chem 1997 40 3254-3262. 

GABA is the predominant intrinsic transmitter of the basal ganglia. Inhibition and disinhibition are considered to be the most important modes of information transfer in the basal ganglia. Ninety-five percent of all neurons in the striatum are GABAergic medium spiny neurons. These neurons are the striatal output neurons. The medium spiny neurons which give rise to the direct pathway also contain substance P or dynorphin as a co-transmitter, while those striatal output neurons that give rise to the indirect pathway contain enkephalin as a co-transmitter. Most striatal interneurons, as well as neurons in GPe, GPi and SNr are also GABAergic. Because striatal and GPe... 

J. P. Meyer, T. J. Gillespie, S. Horn, V. J. Hruby, T. P. Davis, In vitro Stability of Some Reduced Peptide Bond Pseudopeptide Analogues of Dynorphin A , Peptides 1995, 16, 1215-1219. 

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