Van Liefde I, Van Ermen A, van Witzenburg A, Fraeyman N, Vauquelin G
Department of Protein Chemistry, Free University of Brussels (VUB), Sint-Genesius-Rode, Belgium.
Arch Int Pharmacodyn Ther. 1994 Jan-Feb;327(1):69-86.
The beta-adrenoceptor subtypes which trigger lipolysis in white adipocytes vary markedly between calf and rats, and even between different rat strains. In calf adipocytes, CGP12177, a potent antagonist for beta 1- and beta 2-adrenoceptors (i.e., "classical beta-adrenoceptors") and a partial agonist for atypical beta-adrenoceptors, did not stimulate lipolysis, but inhibited with high affinity (IC50 = 0.66 nM) the lipolytic response to 10 nM isoproterenol. In adipocytes from both Wistar rats and Sprague-Dawley OFA rats, CGP12177 stimulated lipolysis to almost the same extent as isoproterenol. Low concentrations of CGP12177 (3 nM) inhibited part of the lipolytic response to 10 nM isoproterenol in the Sprague-Dawley OFA rat adipocytes, but not in Wistar rats at all ages tested (2-4 weeks, 2-4 months, 24-26 months). Hence, functional beta-adrenoceptors are only classical in calf adipocytes, only atypical in Wistar rat adipocytes and both classical and atypical in Sprague-Dawley OFA rat adipocytes. Binding experiments were performed with 150 pM [125I]CYP. On calf adipocyte membranes, competition binding curves with CGP12177 displayed one high affinity binding site (IC50 = 4.7 nM), whereas the curves for CGP20712 (beta 1-selective antagonist) and ICI118551 (beta 2-selective antagonist) were biphasic. In agreement with the functional data, these results indicate that only beta 1- and beta 2-adrenoceptors are present in calf adipose tissue. For both rat strains, only half of the displaceable [125I]CYP binding sites displayed high affinity for CGP12177 (IC50 = 6.8 to 7.5 nM), and competition binding studies with CGP20712 and ICI118551 indicated that they represent beta 1- and beta 2-adrenoceptors. The remaining [125I]CYP binding sites possessed an about 50 times lower affinity for CGP12177 (IC50 = 260 to 345 nM). They are likely to represent atypical beta-adrenoceptors. It is concluded that the presence and the physiological relevance of beta-adrenoceptor subtypes in adipose tissue may not only be species-related, but also strain-related.
在白色脂肪细胞中引发脂肪分解的β-肾上腺素能受体亚型在小牛和大鼠之间，甚至在不同的大鼠品系之间都有显著差异。在小牛脂肪细胞中，CGP12177是β1和β2肾上腺素能受体（即“经典β-肾上腺素能受体”）的强效拮抗剂，也是非典型β-肾上腺素能受体的部分激动剂，它不会刺激脂肪分解，反而以高亲和力（IC50 = 0.66 nM）抑制对10 nM异丙肾上腺素的脂肪分解反应。在Wistar大鼠和Sprague-Dawley OFA大鼠的脂肪细胞中，CGP12177刺激脂肪分解的程度与异丙肾上腺素几乎相同。低浓度的CGP12177（3 nM）在Sprague-Dawley OFA大鼠脂肪细胞中抑制了部分对10 nM异丙肾上腺素的脂肪分解反应，但在所有测试年龄（2 - 4周、2 - 4个月、24 - 26个月）的Wistar大鼠中均未出现这种情况。因此，功能性β-肾上腺素能受体在小牛脂肪细胞中仅为经典型，在Wistar大鼠脂肪细胞中仅为非典型型，而在Sprague-Dawley OFA大鼠脂肪细胞中则兼具经典型和非典型型。用150 pM [125I]CYP进行结合实验。在小牛脂肪细胞膜上，与CGP12177的竞争结合曲线显示出一个高亲和力结合位点（IC50 = 4.7 nM），而CGP20712（β1选择性拮抗剂）和ICI118551（β2选择性拮抗剂）的曲线是双相的。与功能数据一致，这些结果表明小牛脂肪组织中仅存在β1和β2肾上腺素能受体。对于这两种大鼠品系，只有一半的可置换[125I]CYP结合位点对CGP12177显示出高亲和力（IC50 = 6.8至7.5 nM），并且与CGP20712和ICI118551的竞争结合研究表明它们代表β1和β2肾上腺素能受体。其余的[125I]CYP结合位点对CGP12177的亲和力低约50倍（IC50 = 260至345 nM）。它们可能代表非典型β-肾上腺素能受体。得出的结论是，脂肪组织中β-肾上腺素能受体亚型的存在及其生理相关性不仅可能与物种有关，还可能与品系有关。
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