Regulation of Neuronal Function by Ras-GRF Exchange Factors.
Regulation of Neuronal Function by Ras-GRF Exchange Factors.
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DOI：
10.1177/1947601911408077
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发表时间：
2011-03-01
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影响因子：
--
通讯作者：
Feig, Larry A
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作者：
Feig, Larry A
RAS-GRF1(GRF1)和RAS-GRF2(GRF2)是鸟嘌呤核苷酸交换因子家族。主要的异构体p140-GRF1和p135-GRF2有两个全球环境基金结构域，使它们有能力激活Ras和Rac GTPase，以响应来自各种神经递质受体的信号。GRF1和GRF2蛋白主要在中枢神经系统的成年神经元中发现，尽管它们也可以在少数其他组织中检测到。P140-GRF1和p135-GRF2含有钙/钙调素结合的IQ结构域，使它们能够作为钙传感器来介导NMDA型和钙渗透型AMPA型谷氨酸受体的作用。P140-GRF1还通过cAMP介导多巴胺受体的作用。尽管p140-GRF1和p135-GRF2具有相似的功能域，但对GRF基因敲除小鼠的研究表明，它们在调节MAP激酶家族成员、神经元突触可塑性、特定形式的学习和记忆以及对精神活性药物的行为反应方面可以发挥显著不同的作用。此外，GRF蛋白的功能在大脑的不同区域可能有所不同。产生更小的GRF1基因异构体和更少功能结构域的选择性剪接变体也存在；然而，它们在神经元中的不同作用尚未被揭示。对这些蛋白质的持续研究应该会对大脑功能的生化基础产生重要的见解，并产生新的概念来解释复杂的信号转导蛋白，如RAS-GRFs，如何将多个上游信号整合到特定的下游输出中，以控制大脑功能。
Ras-GRF1 (GRF1) and Ras-GRF2 (GRF2) constitute a family of guanine nucleotide exchange factors (GEFs). The main isoforms, p140-GRF1 and p135-GRF2, have 2 GEF domains that give them the capacity to activate both Ras and Rac GTPases in response to signals from a variety of neurotransmitter receptors. GRF1 and GRF2 proteins are found predominantly in adult neurons of the central nervous system, although they can also be detected in a limited number of other tissues. p140-GRF1 and p135-GRF2 contain calcium/calmodulin-binding IQ domains that allow them to act as calcium sensors to mediate the actions of NMDA-type and calcium-permeable AMPA-type glutamate receptors. p140-GRF1 also mediates the action of dopamine receptors that signal through cAMP. Although p140-GRF1 and p135-GRF2 have similar functional domains, studies of GRF knockout mice show that they can play strikingly different roles in regulating MAP kinase family members, neuronal synaptic plasticity, specific forms of learning and memory, and behavioral responses to psychoactive drugs. In addition, the function of GRF proteins may vary in different regions of the brain. Alternative splice variants yielding smaller GRF1 gene isoforms with fewer functional domains also exist; however, their distinct roles in neurons have not been revealed. Continuing studies of these proteins should yield important insights into the biochemical basis of brain function as well as novel concepts to explain how complex signal transduction proteins, like Ras-GRFs, integrate multiple upstream signals into specific downstream outputs to control brain function.