Sökning: WFRF:(Irvine E) >
Mechanism and prope...
Mechanism and properties of positive allosteric modulation of N-methyl-D-aspartate receptors by 6-alkyl 2-naphthoic acid derivatives
-
Sapkota, K. (författare)
-
Irvine, M. W. (författare)
-
Fang, G. Y. (författare)
-
visa fler...
-
Burnell, E. S. (författare)
-
Bannister, N. (författare)
-
Volianskis, A. (författare)
-
- Culley, Georgia, 1988 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology
-
Dravid, S. M. (författare)
-
Collingridge, G. L. (författare)
-
Jane, D. E. (författare)
-
Monaghan, D. T. (författare)
-
visa färre...
-
(creator_code:org_t)
- Elsevier BV, 2017
- 2017
- Engelska.
-
Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 125, s. 64-79
- Relaterad länk:
-
https://europepmc.or...
-
visa fler...
-
https://gup.ub.gu.se...
-
https://doi.org/10.1...
-
visa färre...
Abstract
Ämnesord
Stäng
- The theory that N-methyl-D-aspartate receptor (NMDAR) hypofunction is responsible for the symptoms of schizophrenia is well supported by many pharmacological and genetic studies. Accordingly, positive allosteric modulators (PAMs) that augment NMDAR signaling may be useful for treating schizophrenia. Previously we have identified several NMDAR PAMs containing a carboxylic acid attached to naphthalene, phenanthrene, or coumarin ring systems. In this study, we describe several functional and mechanistic properties of UBP684, a 2-naphthoic acid derivative, which robustly potentiates agonist responses at each of the four GluN1a/GluN2 receptors and at neuronal NMDARs. UBP684 increases the maximal L-glutamate/glycine response while having minor subunit-specific effects on agonist potency. PAM binding is independent of agonist binding, and PAM activity is independent of membrane voltage, redox state, and the GIuN1 exon 5 N-terminal insert. UBP684 activity is, however, markedly pH-dependent, with greater potentiation occurring at lower pHs and inhibitory activity at pH 8.4. UBP684 increases channel open probability (P-o) and slows receptor deactivation time upon removal of L-glutamate, but not glycine. The structurally related PAM, UBP753, reproduced most of these findings, but did not prolong agonist removal deactivation time. Studies using cysteine mutants to lock the GluN1 and GluN2 ligand-binding domains (LBDs) in the agonist-bound states indicate that PAM potentiation requires GluN2 LBD conformational flexibility. Together, these findings suggest that UBP684 and UBP753 stabilize the GluN2 LBD in an active conformation and thereby increase P-o. Thus, UBP684 and UBP753 may serve as lead compounds for developing agents to enhance NMDAR activity in disorders associated with NMDAR hypofunction. (C) 2017 Elsevier Ltd. All rights reserved.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- L-glutamate
- N-methyl-D-aspartate
- Potentiator
- Positive allosteric modulator
- Deactivation
- Ligand-
- subunit messenger-rnas
- nmda receptor
- pregnenolone sulfate
- glutamate-receptor
- proton sensitivity
- postmortem brains
- schizophrenia
- channel
- recombinant
- expression
- Neurosciences & Neurology
- Pharmacology & Pharmacy
- esler m
- 1992
- trends in neurosciences
- v15
- p396
- shina m
- 1993
- molecular basis of ion channels and receptors involved in nerve
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
-
Sapkota, K.
-
Irvine, M. W.
-
Fang, G. Y.
-
Burnell, E. S.
-
Bannister, N.
-
Volianskis, A.
-
visa fler...
-
Culley, Georgia, ...
-
Dravid, S. M.
-
Collingridge, G. ...
-
Jane, D. E.
-
Monaghan, D. T.
-
visa färre...
- Om ämnet
-
- MEDICIN OCH HÄLSOVETENSKAP
-
MEDICIN OCH HÄLS ...
-
och Medicinska och f ...
-
och Neurovetenskaper
- Artiklar i publikationen
-
Neuropharmacolog ...
- Av lärosätet
-
Göteborgs universitet