Dual role of histamine in modulation of Leydig cell steroidogenesis via HRH1 and HRH2 receptor subtypes
Dual role of histamine in modulation of Leydig cell steroidogenesis via HRH1 and HRH2 receptor subtypes
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DOI：
10.1095/biolreprod.105.041285
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发表时间：
2005-11-01
影响因子：
3.6
通讯作者：
Pignataro, O
中科院分区：
文献类型：
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作者：
Mondillo, C;Patrignani, Z;Pignataro, O
虽然有一些报道表明组胺（HA）对女性生殖功能的影响，但很少有文献表明HA在男性性腺中的生理作用。在本研究中，我们报道了HA对MA-10小鼠间质细胞和纯化大鼠间质细胞中类固醇生成的双重浓度依赖性作用。虽然1 nM的HA可以刺激这些细胞产生类固醇并显著增加对LH/hCG的反应，但10 μ M的HA具有抑制作用。我们还在两种实验模型中提供了功能性HRH1和HRH2受体存在的确凿证据。HRH1和HRH2选择性激动剂和拮抗剂的使用使我们认为HRH2的激活将在很大程度上刺激类固醇生成，而HRH1的激活是抑制类固醇合成所必需的。我们关于与这些受体相关的信号转导途径的研究结果表明，HRH2通过与Gs蛋白的直接相互作用与腺苷酸环化酶系统偶联。此外，我们发现HRH1激活介导肌醇磷酸产生的增加，可能是由于该受体与Gq蛋白和磷脂酶C激活的偶联。本报告收集的数据清楚地表明，HA可以调节睾丸间质细胞的类固醇生成，并提示HA可能的新的生理作用部位。鉴于许多结合HRH1、HRH2或两者结合的药物被广泛用于治疗各种ha相关病理，似乎有必要增加对睾丸功能的组胺能调节的了解，以避免这些物质在睾丸中可能出现的意想不到的副作用。
Although several reports indicate effects of histamine (HA) on female reproductive functions, scant literature exists to suggest a physiological role of HA in the male gonad. In the present study, we report a dual concentration-dependent effect of HA on steroidogenesis in MA-10 murine Leydig cells and purified rat Leydig cells. Although 1 nM HA can stimulate steroid production and significantly increase the response to LH/hCG in these cells, 10 mu M HA exerts an inhibitory effect. We also provide confirming evidence for the existence of functional HRH1 and HRH2 receptors in both experimental models. The use of HRH1 and HRH2 selective agonists and antagonists led us to suggest that HRH2 activation would be largely responsible for stimulation of steroidogenesis, while HRH1 activation is required for inhibition of steroid synthesis. Our results regarding signal transduction pathways associated with these receptors indicate the coupling of HRH2 to the adenylate cyclase system through direct interaction with a Gs protein. Moreover, we show HRH1 activation mediates increases in inositol phosphate production, possibly due to coupling of this receptor to Gq protein and phospholipase C activation. The data compiled in this report clearly indicate that HA can modulate Leydig cell steroidogenesis in the testis and suggest a possible new physiological site of action for HA. Given that many drugs binding to HRH1, HRH2, or both, are widely prescribed for the treatment of diverse HA-related pathologies, it seems necessary to increase the knowledge regarding histaminergic regulation of testicular functions, to avoid possible unexpected side effects of such substances in the testis.