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Signaling via Orexin Receptors: A Pharmacological Study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The orexin receptors are a pair of newly discovered G-protein coupled receptors which are activated by the neuropeptides orexins and play a role in sleep/vigilance, apetite/metabolism and neuroendocrine regulation. On a cellular level receptor activation results in, to name but a few effects, elevation of intracellular calcium and depolarisation. All cellular effects display an uncommon dependence of extracellular Ca2+, which has been shown to be due to influx of extracellular Ca2+ as a primary response.

Here we provide evidence for a high specificity of orexin receptors for orexin peptides over other neuropeptides, despite previous reports of the opposite. Other neuropeptides could neither displace orexin-A from orexin receptors, nor affect functional responses induced by orexin peptides via orexin receptors. In an effort to assess the determinants of orexin-A binding to orexin receptors orexin-A was truncated/mutated and tested for functional responses. It was found that alterations in the orexin-A sequence had more prominent effects on the activation of OX1 than on OX2 receptors.

When the signaling of orexin receptors was investigated in neuron-like cells it was found that they couple to Ca2+-metabolism and PLC activation in a manner similar to that in non-neuronal cells. Investigations of OX1 receptor regulation of adenylyl cyclases showed orexin receptors to have a dual effect on the production of cAMP. A high-affinity inhibitory coupling and a low-affinity stimulatory coupling. The stimulatory coupling was determined to consist of two components, a low potency GS-coupling and a high-potency PKC coupling.

In conclusion we have shown that orexin receptors are preferentially activated by orexin peptides and the receptors couple to Ca2+-metabolism in a similar way in different contexts. Orexin receptors couple to both the phospholipase C and the adenylyl cyclase pathway and to some extent these pathways converge in the production of cAMP.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 40
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1376
Keywords [en]
Physiology, orexin, receptors, calcium, cAMP, adenylyl cyclases
Keywords [sv]
Fysiologi
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-4570ISBN: 91-554-6049-6 (print)OAI: oai:DiVA.org:uu-4570DiVA, id: diva2:165154
Public defence
2004-12-18, B21, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-11-25 Created: 2004-11-25 Last updated: 2018-01-13Bibliographically approved
List of papers
1. High specificity of human orexin receptors for orexins over Neuropeptide Y and other neuropeptides
Open this publication in new window or tab >>High specificity of human orexin receptors for orexins over Neuropeptide Y and other neuropeptides
2001 In: Neuroscience Letters, ISSN 0304-3940, Vol. 305, no 3, p. 177-180Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92169 (URN)
Available from: 2004-11-25 Created: 2004-11-25Bibliographically approved
2. Distinct Recognition of OX1 and OX2 Receptors by Orexin Peptides
Open this publication in new window or tab >>Distinct Recognition of OX1 and OX2 Receptors by Orexin Peptides
Show others...
2003 (English)In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 305, no 2, p. 507-514Article in journal (Refereed) Published
Abstract [en]

In this study, we have compared the abilities of orexin-A and orexin-B and variants of orexin-A to activate different Ca(2+) responses (influx and release) in human OX(1) and OX(2) receptor- expressing Chinese hamster ovary cells. Responses mediated by activation of both receptor subtypes with either orexin-A or -B were primarily dependent on extracellular Ca(2+), suggesting similar activation of Ca(2+) influx as we have previously shown for orexin-A and OX(1) receptors. Amino acid-wise truncation of orexin-A reduced its ability to activate OX(1) and OX(2) receptors, but the response mediated by the OX(2) receptor was more resistant to truncation than the response mediated by the OX(1) receptor. We also performed a sequential replacement of amino acids 14 to 26 with alanine in the truncated orexin-A variant orexin-A(14-33). Replacement of the same amino acids produced a fall in the potency for each receptor subtype, but the reduction was less prominent for the OX(2) receptor. The most marked reduction was produced by the replacement of Leu20, Asp25, and His26 with alanine. Interestingly, extracellular Ca(2+) dependence of responses to some of the mutated peptides was different from those of orexin-A and -B. The mutagenesis also suggests that although the determinants required from orexin-A for binding to and activation of the receptor are highly conserved between the orexin receptor subtypes, the OX(2) receptor requires fewer determinants. This might in part explain why orexin-B has the affinity and potency equal to orexin-A for this subtype, although it has 10- to 100-fold lower affinity and potency for the OX(1) receptor.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93307 (URN)10.1124/jpet.102.048025 (DOI)12606634 (PubMedID)
Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2017-12-14Bibliographically approved
3. Orexin signaling in recombinant neuron-like cells
Open this publication in new window or tab >>Orexin signaling in recombinant neuron-like cells
2002 In: FEBS Letters, ISSN 00145793, Vol. 526, no 1-3, p. 11-14Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92171 (URN)
Available from: 2004-11-25 Created: 2004-11-25Bibliographically approved
4. OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms
Open this publication in new window or tab >>OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-92172 (URN)
Available from: 2004-11-25 Created: 2004-11-25 Last updated: 2010-01-13Bibliographically approved

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