Characterization And Pharmacology Of Receptors For Gastr
胃受体的表征和药理学
基本信息
- 批准号:6810456
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:CHO cells bombesin like peptide gastrin releasing peptide gastrointestinal hormones hormone inhibitor hormone receptor neuropeptide receptor peptide hormone analog pharmacology protein structure function receptor binding receptor expression receptor sensitivity site directed mutagenesis stimulant /agonist tissue /cell culture
项目摘要
The pharmacology and molecular pharmacology of two groups of gastrointestinal (GI)peptides were investigated. VIP-related peptides [VIP-related peptides [VIP, PACAP] have widespread effects in the GI tract and central nervous system. The actions of VIP-PACAP-related peptides are mediated by three receptors (VPAC1, VPAC2, PACAP-R). Studies in this project are aimed at understanding the molecular basis of action of these different receptors and at developing selective metabolically stable ligands that function as agonists or antagonists. To define the pharmacology of VIP receptors, the VPAC1 and VPAC2 receptors have been cloned and stably transfected in CHO and PANC1 cells. The VIP pharmacophore is being determined for each VPAC-R subtype by alanine and D-amino acid screening, to attempt to identify selective ligands. Last year results for the VPAC1 were reported and this year we have completed the definition of the human and rat VPAC2 pharmacophore. Amino acids in position 3,6,7,10,12,22 and 23 of VIP were essential for high affinity whereas side chains of amino acids in 2,8,9,16,19,20,21,24, and 25 were not essential. Comparison with VPAC1 show side chains in position 7,10,11,22 were more important for high affinity for VPAC2. There were significant species differences between rat and human VPAC2. This study provides a basis for development of simplified VIP analogues and selective ligands for each VPAC subtype. Bombesin-related peptides (gastrin-releasing peptide [GRP], neuromedin B) interact with two distinct receptors (GRP-R, NMB-R) to mediate a number of effects in the GI tract and central nervous sytem (CNS). The aims of this project are to understand the pharmacology, molecular pharmacology, and cell biology of these receptors. Our results demonstrate the critical amino acids in the 3rd extracellular domain (EC-3) are responsible for GRP selectivity. Particularly important is the substitution of the Ile for Phe185 and Ile for Ala198 in the GRPR compared to the NMBR. Site-directed mutagenesis studies showed this selectivity was primarily mediated by hydrogen bonding and pi-cation interactions between these ligands and the receptor. Our results suggest an interaction between the aromatic ring of Phe185 of the GRPR with GRP is the most important for GRP selectivity. Similar studies are now underway with the NMBR.
本文对两组胃肠肽进行了药理学和分子药理学研究。VIP相关肽[VIP相关肽[VIP,PACAP]]在胃肠道和中枢神经系统中具有广泛的作用。VIP-PACAP相关肽的作用由三种受体(VPAC 1、VPAC 2、PACAP-R)介导。本项目的研究旨在了解这些不同受体作用的分子基础,并开发作为激动剂或拮抗剂的选择性代谢稳定配体。为了确定VIP受体的药理学,已经克隆了VPAC 1和VPAC 2受体,并在CHO和PANC 1细胞中稳定转染。通过丙氨酸和D-氨基酸筛选确定每种VPAC-R亚型的VIP药效团,以尝试鉴定选择性配体。去年报告了VPAC 1的结果,今年我们已经完成了人和大鼠VPAC 2药效团的定义。VIP的3、6、7、10、12、22和23位氨基酸是高亲和力所必需的,而2、8、9、16、19、20、21、24和25位氨基酸的侧链不是必需的。与VPAC 1相比,7、10、11、22位侧链对VPAC 2的高亲和力更重要。大鼠和人VPAC 2之间存在显著的种属差异。本研究为开发简化的VIP类似物和针对各VPAC亚型的选择性配体提供了基础。蛙皮素相关肽(胃泌素释放肽[GRP]、神经介肽B)与两种不同的受体(GRP-R、NMB-R)相互作用,在胃肠道和中枢神经系统(CNS)中介导多种效应。这个项目的目的是了解这些受体的药理学,分子药理学和细胞生物学。我们的研究结果表明,第三胞外结构域(EC-3)中的关键氨基酸负责GRP选择性。特别重要的是与NMBR相比,GRPR中Ile取代Phe 185和Ile取代Ala 198。定点突变研究表明,这种选择性主要是由这些配体和受体之间的氢键和π-阳离子相互作用介导的。我们的研究结果表明,与GRP的GRPR的Phe 185的芳环之间的相互作用是最重要的GRP选择性。类似的研究正在NMBR进行中。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ROBERT JENSEN其他文献
ROBERT JENSEN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ROBERT JENSEN', 18)}}的其他基金
DEVELOP METHODS OF ANALYSIS OF HUMAN COLOSTRUM AND MILK
开发人初乳和乳汁的分析方法
- 批准号:
3652191 - 财政年份:1986
- 资助金额:
-- - 项目类别:
DEVELOP METHODS OF ANALYSIS OF HUMAN COLOSTRUM AND MILK
开发人初乳和乳汁的分析方法
- 批准号:
3652192 - 财政年份:1986
- 资助金额:
-- - 项目类别:
DEVELOP METHODS OF ANALYSIS OF HUMAN COLOSTRUM AND MILK
开发人初乳和乳汁的分析方法
- 批准号:
3652190 - 财政年份:1986
- 资助金额:
-- - 项目类别:
DEVELOP METHODS OF ANALYSIS OF HUMAN COLOSTRUM AND MILK
开发人初乳和乳汁的分析方法
- 批准号:
3652193 - 财政年份:1986
- 资助金额:
-- - 项目类别:
CHARACTERIZATION AND PHARMACOLOGY OF RECEPTORS FOR BOMBESIN RELATED PEPTIDES
铃蟾肽相关肽受体的表征和药理学
- 批准号:
6289813 - 财政年份:
- 资助金额:
-- - 项目类别:
DIAGNOSIS, NATURAL HISTORY AND MANAGEMENT OF GASTRINOMAS
胃泌素瘤的诊断、自然史和治疗
- 批准号:
6432150 - 财政年份:
- 资助金额:
-- - 项目类别:
Pathogenic Factors And Determinants Of Prognosis In Pati
帕蒂的致病因素和预后决定因素
- 批准号:
6546655 - 财政年份:
- 资助金额:
-- - 项目类别:
Characterization And Pharmacology Of Receptors For Bombe
Bombe 受体的表征和药理学
- 批准号:
6546650 - 财政年份:
- 资助金额:
-- - 项目类别:
Diagnosis, Natural History And Management Of Gastrinomas
胃泌素瘤的诊断、自然史和治疗
- 批准号:
6535233 - 财政年份:
- 资助金额:
-- - 项目类别:
相似海外基金
Role of the bombesin-like peptide system in the network regulating energy metabolism
铃蟾肽样肽系统在调节能量代谢网络中的作用
- 批准号:
18500237 - 财政年份:2006
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Analysis of feeding and lipid metabolism regulation by bombesin-like peptide receptors.
铃蟾肽样肽受体的摄食和脂质代谢调节分析。
- 批准号:
15500207 - 财政年份:2003
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Functional clarification of the bombesin-like peptide system.
铃蟾肽样肽系统的功能澄清。
- 批准号:
12680769 - 财政年份:2000
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
INVESTIGATION ON PHYSIOLOGICAL ROLE OF BOMBESIN-LIKE PEPTIDE RECEPTOR SYSTEM IN BRAIN
脑内铃蟾肽样肽受体系统的生理作用研究
- 批准号:
10480222 - 财政年份:1998
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (B).