Endomorphin synthesis in rat brain from intracerebroventricularly injected [3H]-Tyr-Pro: A possible biosynthetic route for endomorphins

Rónai, András Z.; Szemenyei, Erzsébet; Kató, Erzsébet; Kocsis, László; Orosz, György; Al-Khrasani, Mahmoud; Tóth, Géza

doi:10.1016/j.regpep.2005.12.004

Cited by 23 publications

(19 citation statements)

References 37 publications

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“…However, we expect that current findings likely pertain to regulating endogenous spinal EM2 analgesic functionality since some spinal neurons coexpressing MOR, mERα, mGluR 1 and aromatase are apposed by EM2 varicosities. Although the gene encoding endomorphins has not been found, (1) the human proteome contains two proteins with the sequence of a Gly-extended EM2 that are flanked by Gly-Ser cleavage sites [61], (2) Tyr-Pro, has been proposed to serve as a biosynthetic precursor for EM [86], and (3) the presence of EM1/EM2 in the CNS was demonstrated biochemically via Edman degradation and sequencing, independent of antibody recognition [104]. …”

Section: Discussionmentioning

confidence: 99%

Estrogens synthesized and acting within a spinal oligomer suppress spinal endomorphin 2 antinociception: ebb and flow over the rat reproductive cycle

Liu

Murugaiyan

Storman

et al. 2017

PAIN

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The magnitude of antinociception elicited by intrathecal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, varies across the rat estrous cycle. We now report that phasic changes in analgesic responsiveness to spinal EM2 result from plastic interactions within a novel membrane-bound oligomer containing estrogen receptors (mERs), aromatase (aka estrogen synthase), metabotropic glutamate receptor 1 (mGluR1), and MOR. During diestrus, spinal mERs, activated by locally synthesized estrogens, act with mGluR1 to suppress spinal EM2/MOR antinociception. The emergence of robust spinal EM2 antinociception during proestrus results from the loss of mER-mGluR1 suppression, a consequence of altered interactions within the oligomer. The chemical pairing of aromatase with mERs within the oligomer containing MOR and mGluR1 allows estrogens to function as intracellular messengers whose synthesis and actions are confined to the same signaling oligomer. This form of estrogenic signaling, which we term “oligocrine,” enables discrete, highly compartmentalized estrogen/mER-mGluR1 signaling to regulate MOR-mediated antinociception induced by EM2. Finally, spinal neurons were observed not only to coexpress MOR, mERα, aromatase, and mGluR1 but also be apposed by EM2 varicosities. This suggests that modulation of spinal analgesic responsiveness to exogenous EM2 likely reflects changes in its endogenous analgesic activity. Analogous suppression of spinal EM2 antinociception in women (eg, around menses, comparable with diestrus in rats) as well as the (pathological) inability to transition out of that suppressed state at other menstrual cycle stages could underlie, at least in part, the much greater prevalence and severity of chronic pain in women than men.

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Section: Discussionmentioning

confidence: 99%

Estrogens synthesized and acting within a spinal oligomer suppress spinal endomorphin 2 antinociception: ebb and flow over the rat reproductive cycle

Liu

Murugaiyan

Storman

et al. 2017

PAIN

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“…These results demonstrated that the EM1 and EM2 can be widely observed in various regions of CNS and in tissues outside the CNS. In contrast to the case of other endogenous opioid peptides, their biosynthetic pathway is unknown to date; however, a possible route of the biosynthesis was recently suggested for these tetrapeptides [8]. The EMs are highly active and selective MOR agonists, which possess several important biological effects and modulate a variety of physiological processes through the activation of membranebound MOR [3 -5].…”

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confidence: 99%

Structural Investigation of Endomorphins by Experimental and Theoretical Methods: Hunting for the Bioactive Conformation

Leitgeb

2007

Chemistry & Biodiversity

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“…The Drosophila protein, Ebony, is a non-ribosomal peptide synthetase for the conjugation of β-alanine with biogenic amines (Richardt et al, 2003). Ronai et al (2006) proposed that endomorphins may be produced by a de novo synthetic route involving reversal of peptidehydrolase catalytic activities, based on incorporation in rat brain of intracerebroventricularly injected [ 3 H]-Tyr-Pro, however, a radioactive peptide with the HPLC retention time of endomorphin-1 was never observed in 15 experimental samples, and a peptide with the retention time of endomorphin-2 was observed in only 1 of 15 experimental samples. Clearly, this proposed endomorphin de novo biosynthetic pathway requires more robust experimental support, including chemical identity of the peptides with the incorporated label.…”

Section: Discussionmentioning

confidence: 99%

Search of the human proteome for endomorphin-1 and endomorphin-2 precursor proteins

Terskiy

Wannemacher²,

Yadav

et al. 2007

Life Sciences

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Based on the promising opioid pharmacological profile of the peptide, Tyr-Pro-Trp-Gly-NH 2 (Tyr-W-MIF), Zadina et al. (1997) synthesized and screened other Gly 4 -substituted peptides, culminating in the synthesis of Tyr-Pro-Trp-Phe-NH 2 (endomorphin-1), which displayed high affinity and selectivity for the μ opioid receptor. The amidated peptide was then isolated from bovine brain frontal cortex, as was a related peptide, Tyr-Pro-Phe-Phe-NH 2 (endomorphin-2), that displayed similar high affinity and selectivity for the μ opioid receptor. The biosynthesis of the endomorphins in the brain remains obscure, since the putative precursor proteins for the peptides have not been identified. With the completion of the human genome sequencing project, we hypothesized that we should uncover the biological precursors of the peptides using a bioinformatic approach to search the entire human proteome for proteins that contained the endomorphin peptide sequences followed by Gly-Lys/Arg, the consensus sequence for peptide α-amidation and precursor cleavage. Twelve proteins were identified that contained the endomorphin-1 Tyr-Pro-Trp-Phe sequence, however none contained the Tyr-Pro-Trp-Phe-Gly sequence necessary for α-amidation. Twenty-two distinct proteins contained the endomorphin-2 tetrapeptide sequence, and two of those contained the sequence, Tyr-Pro-PhePhe-Gly, however, none contained the requisite peptide-Gly-Lys/Arg sequence. Western blot analysis using an endomorphin-2 antibody detected 4 prominent proteins in mouse brain, necessitating reinterpretation of previous immunocytolocalization studies in the brain. Screening of the current human proteome yielded no evidence for endomorphin precursor proteins based on accepted biochemical criteria.

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Endomorphin synthesis in rat brain from intracerebroventricularly injected [3H]-Tyr-Pro: A possible biosynthetic route for endomorphins

Cited by 23 publications

References 37 publications

Estrogens synthesized and acting within a spinal oligomer suppress spinal endomorphin 2 antinociception: ebb and flow over the rat reproductive cycle

Estrogens synthesized and acting within a spinal oligomer suppress spinal endomorphin 2 antinociception: ebb and flow over the rat reproductive cycle

Structural Investigation of Endomorphins by Experimental and Theoretical Methods: Hunting for the Bioactive Conformation

Search of the human proteome for endomorphin-1 and endomorphin-2 precursor proteins

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