Tags

Type your tag names separated by a space and hit enter

Allosteric modulation of 5-HT(1A) receptors by zinc: Binding studies.
Neuropharmacology. 2009 Feb; 56(2):455-62.N

Abstract

5-HT(1A) receptors were studied via [(3)H]WAY-100635 and [(3)H]8-OH-DPAT binding to rat brain cortical membranes. We characterized the effect of zinc (Zn(2+)) on the binding properties of the 5-HT(1A) receptor. The allosteric ternary complex model was applied to determine the dissociation constant (K(A)) of Zn(2+) and their cooperativity factors (alpha) affecting the dissociation constants (K(D), K(i)) of [(3)H]WAY-100635, [(3)H]8-OH-DPAT, and serotonin (5-HT), the endogenous neurotransmitter. Zn(2+) (5microM-1mM) inhibited the binding of agonist/antagonist to 5-HT1A receptors, mostly by decreasing both the ligands' affinity and the maximal number of sites. In [(35)S]GTPgammaS binding assays Zn(2+) behaved as insourmountable antagonist of 5-HT1A receptors, in agreement with radioligand binding assays. The residues involved in the formation of the inhibitory binding site on the 5-HT1A receptor were assessed by using N-ethyl-maleimide (NEM) or diethylpyrocarbonate (DEPC) which modify preferentially cysteine and histidine residues, respectively. Exposure to both agents did not block the negative allosteric effects of Zn(2+) on agonist and antagonist binding. Our findings represent the first quantitative analysis of allosteric binding interactions for 5-HT(1A) receptors. The physiological significance of Zn(2+) modulation of 5-HT(1A) receptors is unclear, but the colocalization of 5-HT(1A) receptors and Zn(2+) in the nervous system (e.g. in the hippocampus and cerebral cortex) suggests that Zn(2+) released at nerve terminals may modulate signals generated by the 5-HT(1A) receptors in vivo. Finally, these findings suggest that synaptic Zn(2+) may be a factor influencing the effectiveness of therapies that rely on 5-HT(1A) receptor activity.

Authors+Show Affiliations

Departamento de Farmacología, Facultad de Farmacia, Universidad del País Vasco/EHU, Paseo de la Universidad 7, 01006-Vitoria-Gasteiz, Alava, Spain.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18951909

Citation

Barrondo, Sergio, and Joan Sallés. "Allosteric Modulation of 5-HT(1A) Receptors By Zinc: Binding Studies." Neuropharmacology, vol. 56, no. 2, 2009, pp. 455-62.
Barrondo S, Sallés J. Allosteric modulation of 5-HT(1A) receptors by zinc: Binding studies. Neuropharmacology. 2009;56(2):455-62.
Barrondo, S., & Sallés, J. (2009). Allosteric modulation of 5-HT(1A) receptors by zinc: Binding studies. Neuropharmacology, 56(2), 455-62. https://doi.org/10.1016/j.neuropharm.2008.09.018
Barrondo S, Sallés J. Allosteric Modulation of 5-HT(1A) Receptors By Zinc: Binding Studies. Neuropharmacology. 2009;56(2):455-62. PubMed PMID: 18951909.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Allosteric modulation of 5-HT(1A) receptors by zinc: Binding studies. AU - Barrondo,Sergio, AU - Sallés,Joan, Y1 - 2008/10/14/ PY - 2008/07/28/received PY - 2008/09/26/revised PY - 2008/09/29/accepted PY - 2008/10/28/pubmed PY - 2009/7/2/medline PY - 2008/10/28/entrez SP - 455 EP - 62 JF - Neuropharmacology JO - Neuropharmacology VL - 56 IS - 2 N2 - 5-HT(1A) receptors were studied via [(3)H]WAY-100635 and [(3)H]8-OH-DPAT binding to rat brain cortical membranes. We characterized the effect of zinc (Zn(2+)) on the binding properties of the 5-HT(1A) receptor. The allosteric ternary complex model was applied to determine the dissociation constant (K(A)) of Zn(2+) and their cooperativity factors (alpha) affecting the dissociation constants (K(D), K(i)) of [(3)H]WAY-100635, [(3)H]8-OH-DPAT, and serotonin (5-HT), the endogenous neurotransmitter. Zn(2+) (5microM-1mM) inhibited the binding of agonist/antagonist to 5-HT1A receptors, mostly by decreasing both the ligands' affinity and the maximal number of sites. In [(35)S]GTPgammaS binding assays Zn(2+) behaved as insourmountable antagonist of 5-HT1A receptors, in agreement with radioligand binding assays. The residues involved in the formation of the inhibitory binding site on the 5-HT1A receptor were assessed by using N-ethyl-maleimide (NEM) or diethylpyrocarbonate (DEPC) which modify preferentially cysteine and histidine residues, respectively. Exposure to both agents did not block the negative allosteric effects of Zn(2+) on agonist and antagonist binding. Our findings represent the first quantitative analysis of allosteric binding interactions for 5-HT(1A) receptors. The physiological significance of Zn(2+) modulation of 5-HT(1A) receptors is unclear, but the colocalization of 5-HT(1A) receptors and Zn(2+) in the nervous system (e.g. in the hippocampus and cerebral cortex) suggests that Zn(2+) released at nerve terminals may modulate signals generated by the 5-HT(1A) receptors in vivo. Finally, these findings suggest that synaptic Zn(2+) may be a factor influencing the effectiveness of therapies that rely on 5-HT(1A) receptor activity. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/18951909/Allosteric_modulation_of_5_HT_1A__receptors_by_zinc:_Binding_studies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(08)00474-7 DB - PRIME DP - Unbound Medicine ER -