Signaling Diversity Among Gqa Family Members

许多激素和神经递质依赖于Gq类异三聚体G蛋白（Gq/11alpha， G14alpha和G15/16alpha）在靶问题上发挥作用。Gqalpha家族成员激活PLCbeta和肌醇脂质信号，已建立的模型表明这些Galpha的细胞作用是相同的，并且是Ca PKC途径激活的结果。然而，现在有令人信服的证据表明，Gq/11alpha、G14alpha和G15/16alpha在它们的整体细胞反应、与某些蛋白质结合伙伴的相互作用以及它们的细胞和生化特性方面存在显著差异。与已建立的模型相反，我的工作假设是Gq/11alpha， G14alpha和G15/16alpha调节多个重叠和不同的信号级联，并且受到宿主细胞的不同调节，从而引发不同的细胞反应。与这一观点一致的是，Gqalpha家族成员在不同的细胞中表达，Gqalpha除了与PLCbeta外，还与多种信号蛋白相互作用，尽管每种结合伙伴对Gqalpha信号传导的相对贡献尚不清楚。此外，Gq/11alpha， G14alpha和G15/16alpha仅共享57%的氨基酸，并且在其前35个残基（N端）中只有12%的氨基酸相同，这些残基含有调节Galpha信号传导能力所必需的脂肪酸。虽然G14alpha和G15/16alpha的酰化状态是未知的，但序列比对预测Gqalpha家族成员的修饰不同。利用现代分子、细胞和生化方法研究G蛋白的功能，具体目标将是：1。定义Gq/11alpha， G14alpha和G15/16alpha上存在的对调节信号功能重要的生化修饰。2. 定义调节Gq/11alpha、G14alpha和G15/16alpha信号传导能力的因子，包括靶亚细胞定位和与蛋白结合伙伴的相互作用。3. 确定选定细胞中由Gqalpha、G14alpha和G15/16alpha引发的细胞信号反应的多样性，以及Galpha结合伙伴对这些反应的相对贡献。异三聚体G蛋白通过将细胞表面受体与细胞内反应联系起来，在细胞生理学中起着重要作用。G蛋白功能障碍是越来越多的人类疾病的直接原因，目前大多数可用的药物都对G蛋白信号通路起作用。这些实验将确定Gqalpha家族G蛋白之间生化差异的功能相关性，并为这些重要G蛋白引发的信号反应的多样性和调控提供新的见解。从这些研究中获得的信息将帮助我们更好地了解G蛋白作为治疗靶点。

Many hormones and neurotransmitters rely on the Gq class of heterotrimeric G proteins (Gq/11alpha, G14alpha, and G15/16alpha) to exert their actions at target issues. Gqalpha family members activate PLCbeta and inositol lipid signaling, and established models suggest that the cellular actions of these Galpha are identical and result from activation of Ca PKC pathways. However compelling evidence now indicated that Gq/11alpha, G14alpha, and G15/16alpha differ markedly in their overall cellular responses, their interactions with certain protein binding partners, and their cellular and biochemical properties. Contrary to established models, my working hypothesis is that Gq/11alpha, G14alpha and G15/16alpha regulate multiple overlapping and distinct signaling cascades, and are regulated differently by host cells to elicit a distinct profile of cellular responses. Consistent with this idea, Gqalph family members are expressed in different cells, and Gqalpha interacts with multiple signaling proteins besides PLCbeta, though the relative contribution of each binding partner to Gqalpha signaling is unknown. Furthermore, Gq/11alpha, G14alpha and G15/16alpha share only 57 percent overall amino acid identity, and just 12 percent identity within their first 35 residues (N- terminus) which contains fatty acids that are essential for regulating Galpha signaling capacity. Although the acylation state of G14alpha and G15/16alpha is unknown, sequence alignments predict that Gqalpha family members are modified differently. Using modem molecular, cellular, and biochemical approaches study G protein functions, the specific aims will be to: 1. Define biochemical modifications present on Gq/11alpha, G14alpha, and G15/16alpha important for regulating signaling functions. 2. Define factors that regulate Gq/11alpha, G14alpha and G15/16alpha signaling capacity including target subcelluar localization and interactions with protein binding partners. 3. Determine the diversity of cell signaling responses elicited by Gqalpha, G14alpha and G15/16alpha in selected cells, and the relative contribution of Galpha binding partners to those responses. Heterotrimeric G proteins serve essential roles in cell physiology by inking cell surface receptors to intracellular responses. G protein dysfunction is the direct cause of a growing list of human diseases, and the majority of currently available drugs exert their actions on G protein signaling pathways. These experiments will determine functional correlates for the biochemical differences observed among the Gqalpha family of G proteins, and offer new insights into the diversity and regulation of signaling responses elicited by these important G proteins. Information gained from these studies will help us to better understand G proteins as therapeutic targets.