Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nociceptin, also known as orphanin FQ, was recently identified as the naturally occurring agonist of orphan opioid receptor-like ORL1 receptor (Meunier et al., 1995, Nature 377, 532; Reinscheid et al., 1995, Science 270, 792). Nociceptin is a heptadecapeptide which, although it resembles dynorphin A, the endogenous agonist of the kappa-opioid receptor, displays very low potency in competing with binding of [3H]diprenorphine to or inhibiting adenylate cyclase via mu-, delta- and kappa-opioid receptors. Tritium-labeled nociceptin ([3H]nociceptin) was used here to establish a pharmacological profile in vitro of the ORL 1 receptor. In membranes from recombinant Chinese hamster ovary (CHO) cells expressing the ORL 1 receptor, equilibrium binding of [3H]nociceptin is highly specific, saturable (Bmax in the range 1.3-1.8 pmol/mg protein) and of high affinity (Kd approximately equal to 0.1 nM). It is selectively decreased in the presence of Na+ ions and/or of the GTP analog 5'-guanylylimido-diphosphate, an allosteric regulation that is analogous to that of opiate binding to opioid receptors. A few opiates, namely lofentanil, a 4-anilinopiperidine derivative and etorphine, a 6,14-endo-ethenotetrahydrothebaine derivative, were found to be quite potent not only in competing with binding of [3H]nociceptin at the ORL 1 receptor but also in inhibiting forskolin-induced accumulation of cyclic AMP in intact recombinant CHO cells. In a preliminary attempt to delineate active parts of the neuropeptide, nociceptin analogs were also tested, including N- and C-terminal truncation products. Our results suggest that the highly basic, internal core of nociceptin might be essential in conferring on the peptide both affinity for and activity at the ORL 1 receptor. In this respect, the message and address division of dynorphin A, nociceptin's closest structural analog, do not seem to apply to nociceptin.
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PMID:Recognition and activation of the opioid receptor-like ORL 1 receptor by nociceptin, nociceptin analogs and opioids. 908 91

Nociceptin is a peptide transmitter belonging to the opioid family. Nociceptin has recently attracted considerable interest since it appears to exhibit a number of differences to the other opioids. In the present study, we used a nociceptin antibody to map the distribution of nociceptin in the human trigeminal ganglion. In addition, we studied the nociceptin receptor at mRNA levels by RT-PCR and the vasomotor response to nociceptin in human cerebral vessels using a sensitive in vitro method. About 70% of all neuronal cells in trigeminal ganglia were nociceptin immunopositive. Nociceptin was predominantly (78%) expressed in medium-sized cells (30-60 microm). Nociceptin also distributed in small-sized cells (14% of positive cell bodies; <30 microm) and in large-sized cells (8% of positive cell bodies; >60 microm). Double immunostaining showed that in the human trigeminal ganglion nociceptin colocalized with calcitonin gene-related peptide (CGRP), substance P (SP), nitric oxide synthase (NOS) or pituitary adenylate cyclase activating peptide (PACAP). About 61% of nociceptin positive cells contained CGRP, 54% contained SP, 50% contained NOS and 68% contained PACAP. Immunoreactivity to nociceptin was not detected in human cerebral blood vessels. Reverse transcriptase-polymerase chain reaction detected the expression of nociceptin receptor mRNA in trigeminal ganglia but not in basilar arteries. To further examine whether there are functional nociceptin receptors in human cerebral arteries, a pharmacological study was done, where cerebral arteries revealed strong contractions to 60 mM K(+) and U466166 and strong relaxation to CGRP. Nociceptin failed to elicit contraction or relaxation. In conclusion, nociceptin is expressed in human trigeminal ganglia but not in cerebral blood vessels. Nociceptin is colocalized with CGRP, SP, NOS and PACAP. Nociceptin receptor mRNA is expressed in human trigeminal ganglia but not in basilar arteries. The functional role of nociceptin may be at the presynaptic level.
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PMID:Nociceptin immunoreactivity and receptor mRNA in the human trigeminal ganglion. 1257 78

A series of nociceptin receptor ligands has been investigated in relationship to their capability to promote receptor endocytosis, desensitization (evaluated as inhibition of forskolin-stimulated cAMP production) and compensatory upregulation of adenylyl cyclase activity in CHO-K1 cells expressing the cloned human nociceptin receptor. Nociceptin (NC), [Arg14, Lys15]NC-NH2 and NNC 63-0532 (0.01 nM-10 microM) induce a concentration-dependent endocytosis and recycling of the nociceptin receptor. This mechanism contributes to maintain receptor signaling as it counteracts desensitization development and enhances a compensatory upregulation of adenyl cyclase activity. In contrast, the partial agonists [Phe1,Psi(CH2NH)Gly2]NC(1-13)-NH2, Ac-RYYRIK-NH2 and Ac-RYYRWK-NH2 (up to 100 microM) fail to induce receptor endocytosis and cause a pronounced receptor desensitization that is not influenced by monensin, a blocker of recycling of the internalized receptors.
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PMID:Agonist-regulated endocytosis and desensitization of the human nociceptin receptor. 1640 66