Asp125 and Thr130 in transmembrane domain 3 are major sites of α1b-adrenergic receptor antagonist binding

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  • Takahashi Kazuya
    Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences
  • Hossain Murad
    Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences
  • Ahmed Maruf
    Pharmacy Department, University of Rajshahi
  • Bhuiyan Mohiuddin Ahmed
    Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences
  • Ohnuki Toshio
    Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences
  • Nagatomo Takafumi
    Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences

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タイトル別名
  • Asp125 and Thr130 in Transmembrane Domain 3 Are Major Sites of .ALPHA.1b-Adrenergic Receptor Antagonist Binding
  • Asp125 and Thr130 in transmembrane domain 3 are major sites of a1b adrenergic receptor antagonist binding

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Site-directed mutagenesis was used to investigate the molecular interactions involved in prazosin binding to the human α1b-adrenergic receptor (α1b-AR) receptor. Based on molecular modeling studies, Thr130 and Asp125 in transmembrane region III of the α1b-AR receptor were found to interact with prazosin. Thr130 and Asp125 were mutated to alanine (Ala) and expressed in HEK293 cells. The radioligand [3H]prazosin did not show any binding to Asp125Ala mutant of α1b-AR. Therefore, it was not possible to find any prazosin affinity to the mutant using the radioligand [3H]prazosin. The mutation also abolished phenylephrine-stimulated inositol phosphate (IP) formation of [3H]myo-inositol. On the other hand, the Thr130Ala mutant showed reduced binding affinity for [3H]prazosin (dissociation constant, Kd 674.27 pM versus 90.27 pM for the wild-type receptor) and had reduced affinity for both tamsulosin and prazosin (11-fold and 9-fold, respectively). However, the Thr130Ala mutant receptor retained the ability to stimulate the formation of [3H]myo-inositol. The results provide direct evidence that Asp125 and Thr130 are responsible for the interactions between α1b-AR receptor and radioligand [3H]prazosin as well as tamsulosin.

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