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CL/RAMP2和CL/RAMP3产生药理学特性不同的肾上腺髓质素受体：肾上腺髓质素22 - 52、降钙素基因相关肽8 - 37和BIBN4096BS的作用比较。

CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors: a comparison of effects of adrenomedullin22-52, CGRP8-37 and BIBN4096BS.

作者信息

Hay D L, Howitt S G, Conner A C, Schindler M, Smith D M, Poyner D R

机构信息

Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, UK.

出版信息

Br J Pharmacol. 2003 Oct;140(3):477-86. doi: 10.1038/sj.bjp.0705472. Epub 2003 Aug 26.

DOI:10.1038/sj.bjp.0705472
PMID:12970090
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1574059/
Abstract

Adrenomedullin (AM) has two known receptors formed by the calcitonin receptor-like receptor (CL) and receptor activity-modifying protein (RAMP) 2 or 3: we report the effects of the antagonist fragments of human AM and CGRP (AM22-52 and CGRP8-37) in inhibiting AM at human (h), rat (r) and mixed species CL/RAMP2 and CL/RAMP3 receptors transiently expressed in Cos 7 cells or endogenously expressed as rCL/rRAMP2 complexes by Rat 2 and L6 cells. AM22-52 (10 microM) antagonised AM at all CL/RAMP2 complexes (apparent pA2 values: 7.34+/-0.14 (hCL/hRAMP2), 7.28+/-0.06 (Rat 2), 7.00+/-0.05 (L6), 6.25+/-0.17 (rCL/hRAMP2)). CGRP8-37 (10 microM) resembled AM22-52 except on the rCL/hRAMP2 complex, where it did not antagonise AM (apparent pA2 values: 7.04+/-0.13 (hCL/hRAMP2), 6.72+/-0.06 (Rat2), 7.03+/-0.12 (L6)). On CL/RAMP3 receptors, 10 microM CGRP8-37 was an effective antagonist at all combinations (apparent pA2 values: 6.96+/-0.08 (hCL/hRAMP3), 6.18+/-0.18 (rCL/rRAMP3), 6.48+/-0.20 (rCL/hRAMP3)). However, 10 microM AM22-52 only antagonised AM at the hCL/hRAMP3 receptor (apparent pA2 6.73+/-0.14). BIBN4096BS (10 microM) did not antagonise AM at any of the receptors. Where investigated (all-rat and rat/human combinations), the agonist potency order on the CL/RAMP3 receptor was AM approximately betaCGRP>alphaCGRP. rRAMP3 showed three apparent polymorphisms, none of which altered its coding sequence. This study shows that on CL/RAMP complexes, AM22-52 has significant selectivity for the CL/RAMP2 combination over the CL/RAMP3 combination. On the mixed species receptor, CGRP8-37 showed the opposite selectivity. Thus, depending on the species, it is possible to discriminate pharmacologically between CL/RAMP2 and CL/RAMP3 AM receptors.

摘要

肾上腺髓质素（AM）有两种已知受体，由降钙素受体样受体（CL）和受体活性修饰蛋白（RAMP）2或3组成：我们报告了人AM和降钙素基因相关肽（CGRP）的拮抗剂片段（AM22 - 52和CGRP8 - 37）在Cos 7细胞中瞬时表达的人（h）、大鼠（r）及混合物种的CL/RAMP2和CL/RAMP3受体，或在Rat 2和L6细胞中内源性表达为rCL/rRAMP2复合物时对AM的抑制作用。AM22 - 52（10微摩尔）对所有CL/RAMP2复合物中的AM均有拮抗作用（表观pA2值：7.34±0.14（hCL/hRAMP2），7.28±0.06（Rat 2），7.00±0.05（L6），6.25±0.17（rCL/hRAMP2））。CGRP8 - 37（10微摩尔）与AM22 - 52相似，但在rCL/hRAMP2复合物上除外，在此复合物上它不拮抗AM（表观pA2值：7.04±0.13（hCL/hRAMP2），6.72±0.06（Rat2），7.03±0.12（L6））。在CL/RAMP3受体上，10微摩尔CGRP8 - 37对所有组合均为有效拮抗剂（表观pA2值：6.96±0.08（hCL/hRAMP3），6.18±0.18（rCL/rRAMP3），6.48±0.20（rCL/hRAMP3））。然而，10微摩尔AM22 - 52仅对hCL/hRAMP3受体上的AM有拮抗作用（表观pA2 6.73±0.14）。BIBN4096BS（10微摩尔）对任何受体上的AM均无拮抗作用。在所研究的（全大鼠及大鼠/人组合）情况下，CL/RAMP3受体上激动剂的效价顺序为AM≈βCGRP＞αCGRP。rRAMP3显示出三种明显的多态性，其中没有一种改变其编码序列。本研究表明，在CL/RAMP复合物上，AM22 - 52对CL/RAMP2组合比对CL/RAMP3组合具有显著的选择性。在混合物种受体上，CGRP8 - 37表现出相反的选择性。因此，根据物种不同，有可能在药理学上区分CL/RAMP2和CL/RAMP3 AM受体。

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