Department of Molecular Pharmacology, Atran Laboratories, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Neuron. 2011 Apr 14;70(1):51-65. doi: 10.1016/j.neuron.2011.02.039.
RasGRPs, which load GTP onto Ras and Rap1, are expressed in vertebrate and invertebrate neurons. The functions, regulation, and mechanisms of action of neuronal RasGRPs are unknown. Here, we show how C. elegans RGEF-1b, a prototypical neuronal RasGRP, regulates a critical behavior. Chemotaxis to volatile odorants was disrupted in RGEF-1b-deficient (rgef-1⁻/⁻) animals and wild-type animals expressing dominant-negative RGEF-1b in AWC sensory neurons. AWC-specific expression of RGEF-1b-GFP restored chemotaxis in rgef-1⁻/⁻ mutants. Signals disseminated by RGEF-1b in AWC neurons activated a LET-60 (Ras)-MPK-1 (ERK) signaling cascade. Other RGEF-1b and LET-60 effectors were dispensable for chemotaxis. A bifunctional C1 domain controlled intracellular targeting and catalytic activity of RGEF-1b and was essential for sensory signaling in vivo. Chemotaxis was unaffected when Ca²+-binding EF hands and a conserved phosphorylation site of RGEF-1b were inactivated. Diacylglycerol-activated RGEF-1b links external stimuli (odorants) to behavior (chemotaxis) by activating the LET-60-MPK-1 pathway in specific neurons.
RasGRPs 会将 GTP 加载到 Ras 和 Rap1 上，它们在脊椎动物和无脊椎动物神经元中表达。神经元 RasGRPs 的功能、调节和作用机制尚不清楚。在这里，我们展示了 C. elegans RGEF-1b（一种典型的神经元 RasGRP）如何调节关键行为。在缺乏 RGEF-1b（rgef-1⁻/⁻）的动物中和在 AWC 感觉神经元中表达显性负性 RGEF-1b 的野生型动物中，对挥发性气味的趋化作用被破坏。AWC 特异性表达的 RGEF-1b-GFP 恢复了 rgef-1⁻/⁻ 突变体的趋化性。RGEF-1b 在 AWC 神经元中传播的信号激活了 LET-60（Ras）-MPK-1（ERK）信号级联。其他 RGEF-1b 和 LET-60 效应物对于趋化作用是可有可无的。双功能 C1 结构域控制 RGEF-1b 的细胞内靶向和催化活性，对于体内感觉信号传递是必需的。当 RGEF-1b 的 Ca²+结合 EF 手和保守磷酸化位点失活时，趋化性不受影响。二酰基甘油激活的 RGEF-1b 通过在特定神经元中激活 LET-60-MPK-1 途径，将外部刺激（气味）与行为（趋化性）联系起来。
