Site-Directed Mutagenesis of the Serotonin 5-Hydroxytryptamine_<2C> Receptor : Identification of Amino Acids Responsible for Sarpogrelate 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 sarpogrelate binding to the human 5-Hydroxytryptamine (5-HT)_<2C> receptor. Based on molecular modeling studies, Aspartic acid (Asp) 155[3.32] in transmembrane region III and Serine (Ser) 361[7.46] in transmembrane region VII of the 5-HT_<2C> receptor were found to interact with sarpogrelate. Asp3.32 and Ser7.46 were mutated to alanine (Ala) and expressed in COS-7 cells. The radioligand [^3H] mesulergine did not show any binding to Asp3.32Ala mutant of 5-HT_<2C> receptor. Therefore, it was not possible to find any sarpogrelate affinity to the mutant using [^3H] mesulergine. The mutation also abolished agonist-stimulated IP formation of [^3H]wyo-inositol. Introduction of dual mutation at position Ser7.46 (Asp3.32Ala-Ser7.46Ala) could not restore the function disrupted by the first mutation (Asp3.32Ala). On the other hand, the Ser7.46Ala mutant showed reduced binding affinity for [^3H] mesulergine (K_d 3557pM versus 573pM for the wild-type receptor) and had reduced affinity for sarpogrelate. Moreover, the Ser7.46Ala mutant receptor also showed a great loss of potency for sarpogrelate in inhibiting 5-HT-stimulated IP formation of [^3H]myo-inositol. The results provide direct evidence that Asp3.32 and less importantly, Ser7.46 are responsible for the interaction between 5-HT_<2C> receptor and [^3H] mesulergine as well as sarpogrelate. More interestingly, Ser7.46Ala increases the receptor expression (20-fold vs. wild-type) of the mutant receptors and basal [^3H]myo-inositol formation (2.5-fold vs. wild-type), which indicates that the 5-HT_<2C> receptor could be rendered constitutively active by mutating the amino acid serine at position 7.46 to alanine.
- 公益社団法人日本薬学会の論文
- 2006-08-01
著者
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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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Ahmed Maruf
Pharmacy Department University Of Rajshahi
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Ahmed Maruf
バングラデシュ
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KOMIYAMA Tadazumi
Department of Biochemistry, Niigata College of Pharmacy
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RASHID Mamunur
Department of Pharmacology, Niigata College of Pharmacy
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Rashid M
Department Of Cardiovascular Medicine Graduate School Of Medicine Tohoku University
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Rashid Mamunur
Dep. Of Cardiovascular Medicine Graduate School Of Medicine Tohoku Univ. Jpn
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KAWAKAMI Jun
Department of Materials Science and Technology, Faculty of Science and Technology, Hirosaki Universi
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MUNTASIR Habib
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and A
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NASHIMOTO Masayuki
Department of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences
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Kawakami Jun
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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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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AHMED Maruf
Department of Pharmacology, Niigata University of Pharmacy and Applied Life Sciences
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TAKAHASHI Jyuniti
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and A
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Rashid Mamunur
Pharmaceutical Microbiology Research Laboratory Department Of Pharmacy University Of Rajshahi
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Muntasir Habib
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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Rashid Mamunur
Department Of Cardiovascular Medicine Graduate School Of Medicine Tohoku University
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Nagatomo Takafumi
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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Komiyama Tadazumi
Department Of Biochemistry Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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Nashimoto Masayuki
Department Of Applied Life Sciences Niigata University Of Pharmacy And Applied Life Sciences
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Takahashi Jyuniti
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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Kawakami Jun
Department Of Chemistry Faculty Of Science Hirosaki University
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Hossain Murad
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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