Opioid motifs

Sdentitic studies of opioid neurotransmitters during the 1970s have uncovered a complex and subtle system that exhibited impressive diversity in terms of endogenous ligands for only three major receptors. The opioid peptide precursors were subject to complex post-translational modifications resulting in the synthesis of multiple active peptides all of them sharing the common N-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu), which has been termed the opioid motif. Based on the results of theses studies, the endogenous opioids have been implicated in circuits involved in the control of sensation, emotion, and affect and a role has been ascribed to them in addiction, not only to opiates such as morphine or heroin, but also to alcohol. ... 

Three distinct families of classical opioid peptides have been identified the enkephalins, endorphins, and dynorphins. Each family derives from a distinct precursor protein, prepro-opiome-lanocortin (POMC), preproenkephalin, and preprodynorphin, respectively, which are encoded by distinct genes. Each precursor is subject to complex cleavages and posttranslational modifications that result in the synthesis of multiple active peptides. The opioid peptides share a common amino-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu), the opioid motif. This motif is followed by C-terminal extensions yielding peptides ranging from 5 to 31 residues (Table 21-1). 

A novel endogenous opioid peptide with significant sequence homology to dynorphin A was alternatively termed nociceptin or orphanin FQ (now termed N/OFQ Table 21-1). The substitution of Phe for Tyr in the opioid motif is sufficient to abolish interactions with the three classical opioid peptide receptors. N/OFQ has behavioral and pain modulatory properties distinct from those of the three classical opioid peptides. 

The GPCR C-terminal region, with or without a coiled-coil motif, has been implicated in the heterodimerization process of GABAb(1)-GABAb(2) (78,80), as well as in the homodimerization of 5-opioid receptor (120). However, the possibility cannot be ruled out that the indirect evidence for the involvement of the C-terminal domain results from changes produced by the deletion of the C-terminal tail, that alters the conformation of the receptors and causes decreased interactions between transmembrane helices and oligomer disruption. 

Huang, P., Li, J., Visiers, I., Weinstein, H., and Liu-Chen, L.-Y. (2001) Functional role of a conserved motif in TM6 of the rat m opioid receptor constitutively active and inactive receptors result from substitutions of Thr6.34(279) with Lys and Asp. Biochemistry 40, 13501-13509. 

While GRK2, 3, and 5, phosphorylation has been associated with agonist activation of many receptors (44,137), only discrete regions of phosphorylation that are attributable to one specific enzyme appear to be essential for desensitization (122). With respect to the P -adrenergic (138-141), the dopamine D, (122), the p-opioid (142), the 5-opioid (143), the aj -adrenergic (133), the Aj and adenosine (144-146), and the N-formyl peptide (134) receptors, the motifs may be located in the carboxyl tail. 

Hence, the various motifs on the opioid receptor that are involved in the receptor interaction with other cellular proteins could in turn regulate the trafficking of the receptor. 

Chavkin and Goldstein [3] pointed out that endogenous opioid peptides conform to a message-address motif, and it was suggested that the invariant tetrapeptide sequence Tyr-Gly-Gly-Phe can be viewed as the message while subsequent amino acid residues constitute the address. A modification of this... 

Molecular analysis of the opioid receptors indicates that they conform to the structural motif of the G protein receptor family. All three types of opioid receptors contain cysteine residues believed to be involved in disulfide bonds, and a cysteine fatty acid attachment site in locations common with other G protein-coupled receptors. All three opioid receptors contain consensus asparagine-linked glycosylation sites in the extracellular N-terminal domain as well as many consensus protein kinase sites in the first and third intracellular loops, and in the C-terminal domain. 

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