In vivo gene modification elucidates subtype-specific functions of alpha(2)-adrenergic receptors.
In vivo gene modification elucidates subtype-specific functions of alpha(2)-adrenergic receptors.
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发表时间：
2000-04
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通讯作者：
Joseph W. Kable;L. Murrin;D. Bylund
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作者：
Joseph W. Kable;L. Murrin;D. Bylund
由于缺乏足够的亚型选择性药物，具有改变的α（2）-肾上腺素能受体基因的小鼠已经成为阐明三种α（2）-肾上腺素能受体亚型的亚型特异性功能的重要工具。已经产生了具有α（2A）-、α（2B）-或α（2C）-基因的缺失（敲除）以及α（2A）-基因的点突变（α（2A）-D 79 N）和α（2C）-基因的3倍过表达的小鼠。对这些小鼠的研究表明，大多数由α（2）-肾上腺素能受体介导的经典功能，如低血压、镇静、镇痛、体温过低和麻醉保留效应，主要由α（2A）-亚型介导。α（2B）-亚型是对α（2）-激动剂的高血压反应的主要介质，似乎在盐诱导的高血压中起作用，并且在发育过程中可能很重要。α（2C）亚型似乎参与许多中枢神经系统过程，如惊吓反射，应激反应和运动。α（2A）-和α（2C）-亚型在去甲肾上腺素释放的突触前抑制中都很重要，并且似乎具有不同的调节作用。通过以不同的方式改变相同的α（2）-肾上腺素能受体来研究不同小鼠品系的亚型特异性功能的能力加强了从这些研究中得出的结论。虽然这些遗传学方法有局限性，但它们显著增加了我们对α 2肾上腺素能受体亚型功能的理解。
Mice with altered alpha(2)-adrenergic receptor genes have become important tools in elucidating the subtype-specific functions of the three alpha(2)-adrenergic receptor subtypes because of the lack of sufficiently subtype-selective pharmacological agents. Mice with a deletion (knockout) of the alpha(2A)-, alpha(2B)-, or alpha(2C)-gene as well as a point mutation of the alpha(2A)-gene (alpha(2A)-D79N) and a 3-fold overexpression of the alpha(2C)-gene have been generated. Studies with these mice indicate that most of the classical functions mediated by the alpha(2)-adrenergic receptor, such as hypotension, sedation, analgesia, hypothermia, and anesthetic-sparing effect, are mediated primarily by the alpha(2A)-subtype. The alpha(2B)-subtype is the principal mediator of the hypertensive response to alpha(2)-agonists, appears to play a role in salt-induced hypertension, and may be important in developmental processes. The alpha(2C)-subtype appears to be involved in many central nervous system processes such as the startle reflex, stress response, and locomotion. Both the alpha(2A)- and alpha(2C)-subtypes are important in the presynaptic inhibition of norepinephrine release and appear to have distinct regulatory roles. The ability to study subtype-specific functions in different mouse strains by altering the same alpha(2)-adrenergic receptor in different ways strengthens the conclusions drawn from these studies. Although these genetic approaches have limitations, they have significantly increased our understanding of the functions of alpha(2)-adrenergic receptor subtypes.