GABA-A RECEPTOR STRUCTURE AND FUNCTION

GABAA受体(GABAR)介导了中枢神经系统(CNS)的大部分快速抑制性突触传递，因此对正常和疾病的CNS功能至关重要。有一类相似但不同的GABAR亚型，它们在药理和生物学特性上有所不同。此外，GABAR存在于神经元细胞膜、突触培养物和非突触膜的不同部位。突触受体的贩运、靶向、聚集和周转的研究才刚刚开始。特别是，与GABAR细胞内结构域相互作用的细胞蛋白可能起到锚定和聚集突触上的受体的作用，以及在可塑性事件中建立和重建突触及其受体。我们将研究几种与GABAR相互作用的细胞蛋白的功能，这些蛋白是我们使用酵母双杂交系统鉴定的。GABARAP(GABA受体相关蛋白)将GABAR Gamma2亚单位与微管连接，并在突触处聚集GABAR。RACK1(激活的C-激酶受体)将蛋白激酶C-β连接到GABARα1亚单位，可能通过与PKC的蛋白磷酸化来调节GABAR功能的某一方面。对这些和相关蛋白质的研究将使我们能够近距离观察这些重要的大脑神经递质受体的动态和重要的细胞生物学。

GABAA receptors (GABAR) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system (CNS), and are thus critical to normal and disease CNS function. There are a family of similar but distinct GABAR subtypes which vary in pharmacological and biological properties. In addition GABAR are located in different parts of the neuronal cell membrane and in synaptic cultures as well as non- synaptic membrane. The trafficking, targeting, clustering, and turnover of synaptic receptors in just beginning to be studied. In particular, cellular proteins that interact with the intracellular domains of GABAR may serve to anchor and cluster receptors at synapses at synapses, as well as to establish and reconstruct synapses and their receptors during plasticity events. We will study the function of several cellular proteins that interact with GABAR that we identified using the yeast two-hybrid system. GABARAP (GABA Receptor Associated Protein) links GABAR gamma2 subunit to microtubules and clusters GABAR at synapses. RACK1 (receptor for activated C-kinase), links protein kinase C-beta to GABAR alpha1 subunit, probably for regulating some aspect of GABAR function by protein phosphorylation with PKC. Studies on these and related proteins will allow us to take a close look a dynamic and important cellular biology of these important brain neurotransmitter receptors.