Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals.
Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals.
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DOI：
10.1677/joe-07-0541
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发表时间：
2008-05
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影响因子：
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通讯作者：
Yoshio Takei;H. Hashimoto;Koji Inoue;T. Osaki;K. Yoshizawa‐Kumagaye;M. Tsunemi;T. Watanabe;M. Ogoshi;Naoto Minamino;Yoichi Ueta
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文献类型：
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作者：
Yoshio Takei;H. Hashimoto;Koji Inoue;T. Osaki;K. Yoshizawa‐Kumagaye;M. Tsunemi;T. Watanabe;M. Ogoshi;Naoto Minamino;Yoichi Ueta
肾上腺髓质素5（AM 5）是在硬骨鱼中发现的降钙素基因相关肽（CGRP）家族的新成员。虽然在哺乳动物基因组数据库中已经发现了AM 5的存在，但其分子身份和生物学功能尚未得到研究。在这项研究中，我们克隆了编码猪AM 5的cDNA，并研究了其对心血管和肾脏的影响。推测成熟的AM 5定位于激素原的中间，并具有分子间环形成和C-末端酰胺化的潜在信号。AM 5基因在脾脏和胸腺中表达最丰富。在哺乳动物数据库中发现了几个新的AM 5基因，揭示了AM 5基因存在于灵长类、食肉动物和波动动物中，但在啮齿类中未发现。在灵长类动物中，在从恒河猴过渡到灵长类动物（人类和黑猩猩）的成熟AM 5序列中发生了核苷酸缺失。将合成的成熟AM 5静脉内注射到大鼠中，以0.1-1 nmol/kg诱导动脉压的剂量依赖性降低，而心率没有明显变化。在1分钟内降低最大，AM 5的效力约为AM的一半。AM 5在任何剂量下均未引起尿流量和尿Na+浓度的显著变化。与外周血管降压作用相反，注射入脑室的AM 5在0.1-1 nmol时剂量依赖性地增加动脉压和心率。AM 5（5 min）后的增加比AM（15-20 min）更快达到最大值。将AM 5与一种受体活性修饰蛋白（RAMP）一起加入表达降钙素受体样受体（CGRP）或降钙素受体（CTR）的培养细胞中，其组合形成CGRP家族的主要受体，在任何组合中均不诱导cAMP产生的明显增加，尽管当加入到RAMP和RAMP 2/3组合中时，AM在10（-）（10）-10（-）（9）M时使其增加。这些数据表明，AM 5似乎作用于AM 5的一种或多种未知受体，而不是AM 5/CTR+RAMP，以在哺乳动物中发挥中枢和外周心血管作用。
Adrenomedullin 5 (AM5) is a new member of the calcitonin gene-related peptide (CGRP) family identified in teleost fish. Although its presence was suggested in the genome database of mammals, molecular identity and biological function of AM5 have not been examined yet. In this study, we cloned a cDNA encoding AM5 in the pig and examined its cardiovascular and renal effects. Putative mature AM5 was localized in the middle of prohormone and had potential signals for intermolecular ring formation and C-terminal amidation. The AM5 gene was expressed most abundantly in the spleen and thymus. Several AM5 genes were newly identified in the database of mammals, which revealed that the AM5 gene exists in primates, carnivores, and undulates but could not be identified in rodents. In primates, nucleotide deletion occurred in the mature AM5 sequence in anthropoids (human and chimp) during transition from the rhesus monkey. Synthetic mature AM5 injected intravenously into rats induced dose-dependent decreases in arterial pressure at 0.1-1 nmol/kg without apparent changes in heart rate. The decrease was maximal in 1 min and AM5 was approximately half as potent as AM. AM5 did not cause significant changes in urine flow and urine Na+ concentration at any dose. In contrast to the peripheral vasodepressor action, AM5 injected into the cerebral ventricle dose-dependently increased arterial pressure and heart rate at 0.1-1 nmol. The increase reached maximum more quickly after AM5 (5 min) than AM (15-20 min). AM5 added to the culture cells expressing calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of the receptor activity-modifying proteins (RAMPs), the combination of which forms major receptors for the CGRP family, did not induce appreciable increases in cAMP production in any combination, although AM increased it at 10(-)(10)-10(-)(9) M when added to the CLR and RAMP2/3 combination. These data indicate that AM5 seems to act on as yet unknown receptor(s) for AM5, other than CLR/CTR+RAMP, to exert central and peripheral cardiovascular actions in mammals.