| RRC ID |
65920
|
| 著者 |
Hishinuma S, Kosaka K, Akatsu C, Uesawa Y, Fukui H, Shoji M.
|
| タイトル |
Asp73-dependent and -independent regulation of the affinity of ligands for human histamine H1 receptors by Na.
|
| ジャーナル |
Biochem Pharmacol
|
| Abstract |
The affinity of ligands for G-protein-coupled receptors (GPCRs) is allosterically regulated by Na+ via a highly conserved aspartate residue (Asp2.50) in the second transmembrane domain of GPCRs. In the present study, we examined the Na+-mediated regulation of the affinity of ligands for Gq/11-protein-coupled human histamine H1 receptors in Chinese hamster ovary cells. The affinities of 3 agonists and 20 antihistamines were evaluated by their displacement curves against the binding of [3H]-mepyramine to membrane preparations in the presence or absence of 100mM NaCl. The affinities of most drugs including histamine, an agonist, and d-chlorpheniramine, a first-generation antihistamine, were reduced by NaCl, with the extent of NaCl-mediated changes varying widely between drugs. In contrast, the affinities of some second-generation antihistamines such as fexofenadine were increased by NaCl. These changes were retained in intact cells. The mutation of Asp2.50 (Asp73) to asparagine abrogated NaCl-induced reductions in affinities for histamine and d-chlorpheniramine, but not NaCl-induced increases in the affinity for fexofenadine. Quantitative structure-activity relationship (QSAR) analyses showed that these Na+-mediated changes were explained and predicted by a combination of the molecular energies and implicit solvation energies of the compounds. These results suggest that Na+ diversely regulates the affinity of ligands for H1 receptors from the extracellular sites of receptors via Asp73-dependent and -independent mechanisms in a manner that depends on the physicochemical properties of ligands. These results may contribute to a deeper understanding of the fundamental mechanisms by which the affinity of ligands for their receptors is allosterically regulated by Na+.
|
| 巻・号 |
128
|
| ページ |
46-54
|
| 公開日 |
2017-3-15
|
| DOI |
10.1016/j.bcp.2016.12.021
|
| PII |
S0006-2952(16)30501-9
|
| PMID |
28040476
|
| MeSH |
Animals
Aspartic Acid / genetics*
CHO Cells
Cations, Monovalent
Chlorpheniramine / pharmacology
Cricetulus
Histamine / pharmacology
Histamine Agonists / pharmacology
Histamine H1 Antagonists / pharmacology
Humans
Ligands
Mutation
Quantitative Structure-Activity Relationship
Radioligand Assay
Receptors, Histamine H1 / genetics
Receptors, Histamine H1 / physiology*
Sodium Chloride / pharmacology*
Terfenadine / analogs & derivatives
Terfenadine / pharmacology
|
| IF |
4.96
|
| リソース情報 |
| ヒト・動物細胞 |
CHO-K1(RCB0285) |
