Calcium-dependent glutamate release from astrocytes

描述(申请人提供)：星形胶质细胞，胶质细胞的一个亚型，表现出一种基于细胞内钙变化的兴奋性。这些细胞内钙的变化，即振荡，可以由神经递质引起。对星形胶质细胞钙振荡的功能影响知之甚少。由于细胞内钙离子水平控制着星形胶质细胞谷氨酸的释放，我们假设钙振荡的频率也控制着这些细胞谷氨酸的释放量。我们将在特定的目标I检验这一假说。神经元上钙依赖的分泌可以被钙下游分泌机制依赖的蛋白激酶A(PKA)和蛋白激酶C(PKC)所调节。由于星形胶质细胞表达负责神经元分泌的分泌机制的核心蛋白，我们推测星形胶质细胞的谷氨酸释放也可能受到依赖于PKA和PKC的分泌机制部位的磷酸化的调节。我们将在《特定目标2》中检验这一假设。 具体目标一：我们将检验星形胶质细胞谷氨酸释放受钙振荡频率控制的假设。 具体目的1：我们将验证PKA和PKC调节星形胶质细胞钙依赖的谷氨酸释放的假说。 这项研究将为星形胶质细胞如何与神经元交流提供新的重要信息。由于星形胶质细胞通过释放谷氨酸来调节突触传递，这种对神经胶质活动的新见解有可能改变我们对中枢神经系统功能和功能障碍的看法

DESCRIPTION (provided by applicant): Astrocytes, a subtype of glial cell, exhibit a form of excitability based on intracellular Ca2+ variations. These intracellular calcium variations, i.e., oscillations can be evoked by neurotransmitters. The functional consequences of calcium oscillations in astrocytes are poorly understood. Since the level of intracellular calcium ions control glutamate release from astrocytes, we hypothesize that the frequency of calcium oscillations also control the amount of glutamate release from these cells. We will test this hypothesis in Specific Aim I. Calcium-dependent secretion in neurons can be modulated by the protein kinase A (PKA)- and protein kinase C (PKC)-dependent phosphorylation of secretory machinery downstream of calcium. Since astrocytes express the core proteins of the secretory machinery responsible for neuronal secretion, we hypothesize that glutamate release from astrocytes may also be modulated by PKA- and PKC-dependent phosphorylation at the site of secretory machinery. We will test this hypothesis in Specific Aim II. Specific Aim I: We will test the hypothesis that glutamate release from astrocytes is controlled by the frequency of calcium oscillations. Specific Aim Il: We will test the hypothesis that PKA and PKC modulate calcium-dependent glutamate release from astrocytes. This study will provide new and important information on how astrocytes communicate with neurons. Since astrocytes modulate synaptic transmission by releasing glutamate, this new insight into glial action has potential to change the way we think about central nervous system functions and dysfunctions