Is the 5-hydroxytryptamine 7 Receptor Constitutively Active in the Vasculature? A Study in Veins/Vein.
Is the 5-hydroxytryptamine 7 Receptor Constitutively Active in the Vasculature? A Study in Veins/Vein.
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DOI：
10.1097/fjc.0000000000001296
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发表时间：
2022-08-01
影响因子：
3
通讯作者：
Thompson, Janice M.
中科院分区：
文献类型：
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作者：
Watts, Stephanie W.;Flood, Emma D.;Thompson, Janice M.
据报道，5-羟色胺7（5-HT 7）受体在转染到细胞中时具有相当大的组成型活性。组成活性-在没有已知激动剂的情况下的受体活性-对于理解受体对（病理）生理学的贡献是重要的。在这里，我们测试的假设，即5-HT 7受体具有组成性活动在生理情况下。雄性和雌性Sprague道利大鼠的离体静脉用作测量等长力的模型;腹腔静脉具有介导舒张的功能性5-HT 7受体，而小肠系膜静脉则没有。研究了报告用作反向激动剂的化合物引起收缩的能力（将组成性活性松弛剂受体移动到非活性状态，消除松弛）。与溶剂对照组相比，氯氮平、利培酮、酮色林和SB 269970在离体雄性腹部腔静脉中未引起收缩。相比之下，甲硫替平引起雄性而非雌性腹腔静脉的浓度依赖性收缩，尽管效力（−log EC 50 [M]= 5.50±0.45）和效力（对内皮素-1收缩的约12%）较低。5-HT 7受体拮抗剂（SB 269970，1 μM，在腔静脉中无活性）未降低甲硫氨酸诱导的收缩。这些相同的化合物在离体肠系膜静脉中几乎没有作用。我们的结论是，5-HT 7受体在离体静脉的Sprague道利大鼠不具有组成性活动。我们提出的问题，这种受体的组成活动的生理相关性，重要的睡眠，昼夜节律，温度和血压调节等不同的生理功能。
The 5-hydroxytryptamine 7 (5-HT7) receptor is reported to have considerable constitutive activity when transfected into cells. Constitutive activity – receptor activity in the absence of known agonist – is important for understanding the contributions of a receptor to (patho)physiology. Here, we test the hypothesis that the 5-HT7 receptor possesses constitutive activity in a physiological situation. Isolated veins from male and female Sprague Dawley rats were used as models for measuring isometric force; the abdominal vena cava possesses a functional 5-HT7 receptor that mediates relaxation while the small mesenteric vein does not. Compounds reported to act as inverse agonists were investigated for their ability to cause contraction (moving a constitutively active relaxant receptor to an inactive state, removing relaxation). Compared to a vehicle control, clozapine, risperidone, ketanserin and SB269970 caused no contraction in the isolated male abdominal vena cava. By contrast, methiothepin caused a concentration-dependent contraction of the male but not female abdominal vena cava, though with low potency (−log EC50 [M]= 5.50±0.45) and efficacy (∼12% of contraction to endothelin-1). Methiothepin-induced contraction was not reduced by the 5-HT7 receptor antagonist (SB269970, 1 μM, not active in the vena cava). These same compounds showed little to no effect in the isolated mesenteric vein. We conclude that the 5-HT7 receptor in the isolated veins of the Sprague Dawley rat does not possess constitutive activity. We raise the question of the physiological relevance of constitutive activity of this receptor important to such diverse physiological functions as sleep, circadian rhythm, temperature and blood pressure regulation.