Abnormal regulation of the sympathetic nervous system in alpha2A-adrenergic receptor knockout mice.
Abnormal regulation of the sympathetic nervous system in alpha2A-adrenergic receptor knockout mice.
复制标题
α2A-肾上腺素受体敲除小鼠交感神经系统的异常调节。
作者：
J. Altman;A. Trendelenburg;L. Macmillan;D. Bernstein;L. Limbird;K. Starke;B. Kobilka;L. Hein
α 2-肾上腺素能受体（AR）在调节中枢和外周交感神经系统中的神经递质释放中起关键作用。迄今为止，已经克隆了三种亚型的α 2-AR（α 2A、α 2B和α 2C）。在这里，我们描述了破坏α 2A-AR基因的生理后果。将缺乏功能性α 2A亚型的小鼠与野生型（WT）小鼠、缺乏α 2B或α 2C亚型的动物以及携带α 2A-AR基因点突变（α 2AD 79 N）的小鼠进行比较。α 2A亚型缺失导致静息心动过速时交感神经活动增加（敲除，581 +/- 21 min-1; WT，395 +/- 21 min-1），心脏组织去甲肾上腺素浓度耗竭（敲除，676 +/- 31 pg/mg蛋白; WT，1178 +/- 98 pg/mg蛋白），以及心脏β-AR的下调（Bmax：敲除，23 +/- 1 fmol/mg蛋白; WT，31 +/- 2 fmol/mg蛋白）。在α 2A缺陷小鼠中，α 2激动剂的肿胀作用完全不存在。突触前α 2-AR功能进行了测试，在两个孤立的输精管准备。非亚型选择性α 2激动剂右美托咪定完全阻断了α 2B-AR敲除、α 2C-AR敲除、α 2AD 79 N突变和WT小鼠输精管对电刺激的收缩反应。在α 2A-AR敲除小鼠中，α 2激动剂对输精管收缩的最大抑制仅为42 +/-9%。在输精管中进行的[3 H]去甲肾上腺素释放研究证实了这些发现。结果表明，α 2A-AR是调节交感神经释放去甲肾上腺素的主要突触前受体亚型;然而，在α 2A-AR敲除小鼠中残留的α 2介导的作用表明，第二种α 2亚型（α 2B或α 2C）也起突触前自身受体的作用，以抑制递质释放。
alpha2-Adrenergic receptors (ARs) play a key role in regulating neurotransmitter release in the central and peripheral sympathetic nervous systems. To date, three subtypes of alpha2-ARs have been cloned (alpha2A, alpha2B, and alpha2C). Here we describe the physiological consequences of disrupting the gene for the alpha2A-AR. Mice lacking functional alpha2A subtypes were compared with wild-type (WT) mice, with animals lacking the alpha2B or alpha2C subtypes, and with mice carrying a point mutation in the alpha2A-AR gene (alpha2AD79N). Deletion of the alpha2A subtype led to an increase in sympathetic activity with resting tachycardia (knockout, 581 +/- 21 min-1; WT, 395 +/- 21 min-1), depletion of cardiac tissue norepinephrine concentration (knockout, 676 +/- 31 pg/mg protein; WT, 1178 +/- 98 pg/mg protein), and down-regulation of cardiac beta-ARs (Bmax: knockout, 23 +/- 1 fmol/mg protein; WT, 31 +/- 2 fmol/mg protein). The hypotensive effect of alpha2 agonists was completely absent in alpha2A-deficient mice. Presynaptic alpha2-AR function was tested in two isolated vas deferens preparations. The nonsubtype-selective alpha2 agonist dexmedetomidine completely blocked the contractile response to electrical stimulation in vas deferens from alpha2B-AR knockout, alpha2C-AR knockout, alpha2AD79N mutant, and WT mice. The maximal inhibition of vas deferens contraction by the alpha2 agonist in alpha2A-AR knockout mice was only 42 +/- 9%. [3H]Norepinephrine release studies performed in vas deferens confirmed these findings. The results indicate that the alpha2A-AR is a major presynaptic receptor subtype regulating norepinephrine release from sympathetic nerves; however, the residual alpha2-mediated effect in the alpha2A-AR knockout mice suggests that a second alpha2 subtype (alpha2B or alpha2C) also functions as a presynaptic autoreceptor to inhibit transmitter release.
人脑中 α-2 肾上腺素受体亚型的表征。
DOI：
--
发表时间：
1993
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Ordway,GA;Jaconetta,SM;Halaris,AE
通讯作者：
Halaris,AE
编码小鼠 α2c-肾上腺素受体同系物的基因的靶向失活。
DOI：
--
发表时间：
1995
期刊：
Molecular pharmacology.
影响因子：
--
作者：
Link,RE;Stevens,MS;Kulatunga,M;Scheinin,M;Barsh,GS;Kobilka,BK
通讯作者：
Kobilka,BK
克隆编码 α2-肾上腺素能受体亚型的两个小鼠基因，并鉴定小鼠 α2-C10 同源物中负责拮抗剂结合的种间变异的单个氨基酸。
影响因子：
3.6
作者：
Link,R;Daunt,D;Barsh,G;Chruscinski,A;Kobilka,B
通讯作者：
Kobilka,B