Asp125 and Thr130 in Transmembrane Domain 3 Are Major Sites of α_<1b>-Adrenergic Receptor Antagonist Binding(Pharmacology)
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概要
- 論文の詳細を見る
Site-directed mutagenesis was used to investigate the molecular interactions involved in prazosin binding to the human α_<1b>-adrenergic receptor (α_<1b>-AR) receptor. Based on molecular modeling studies, Thr130 and Asp125 in transmembrane region III of the α_<1b>-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 α_<1b>-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, K_d 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 α_<1b>-AR receptor and radioligand [^3H] prazosin as well as tamsulosin.
- 公益社団法人日本薬学会の論文
- 2007-10-01
著者
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Takahashi Kazuya
Department of Geriatric Dentistry, Osaka Dental University
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Takahashi Kazuya
Department Of Geriatric Dentistry Osaka Dental University
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BHUIYAN Mohiuddin
Department of Pharmacology, Niigata University of Pharmacy and Applied Life Sciences
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HOSSAIN Murad
Department of Pharmacology, Niigata University of Pharmacy and Applied Life Sciences
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NAGATOMO Takafumi
Department of Pharmacology, Niigata University of Pharmacy and Applied Life Sciences
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長友 孝文
新潟薬科大学薬学部薬理学教室
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Bhuiyan Mohiuddin
Dep. Of Pharmacology Fac. Of Pharmaceutical Sciences Niigata Univ. Of Pharmacy And Applied Life Scie
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Ahmed Maruf
Pharmacy Department University Of Rajshahi
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Ahmed Maruf
バングラデシュ
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Nagatomo T
Dep. Of Pharmacology Fac. Of Pharmaceutical Sciences Niigata Univ. Of Pharmacy And Applied Life Scie
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OHNUKI Toshio
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and A
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大貫 敏男
新潟薬科大学薬理学教室
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Ohnuki Toshio
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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Ohnuki Toshio
Department Of Pharmacology Nilgata College Of Pharmacy
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Nagatomo Takafumi
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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大貫 敏男
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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Ohnuki Toshio
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Hokkaido University
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Bhuiyan Mohiuddin
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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Hossain Murad
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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Takahashi Kazuya
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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Takahashi Kazuya
Department Of Geriatic Dentistry Osaka Dental University
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Takahashi Kazuya
Department Of Chemistry The University Of Tokyo
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