Research Initiation Award Grant for Identifying changes in serotonin receptor function due to naturally occurring single nucleotide polymorphisms (SNPs)

菲斯克大学这个项目的目标是通过检测细微修饰的受体结构，如在人类个体中发现的单核苷酸多态性（snp）编码的受体，来确定可能被5-羟色胺（5-羟色胺；5-HT）受体使用的新的信号通路。本研究的目标是将编码天然多态性5-HT2CRs的cdna引入异源细胞，其序列修饰位于先前确定的与G蛋白介导的信号通路偶联的关键区域，并表征这些snp编码序列修饰的功能后果。每年至少有两名本科生将参与这项研究。此外,主人?实验室里的学生将成为本科生的榜样。该项目将研究5-羟色胺（5-HT） 2C受体的单核苷酸多态性（snp）的功能后果。5-羟色胺是一种神经递质，通过与14种不同受体亚型之一结合来调节多种神经生理反应，其中一种是5-HT2C受体（5-HT2CR）。5-HT2CR是一种跨七膜（7TM）的G蛋白偶联受体（GPCR），参与神经元兴奋性、空间学习和食欲。最近的研究表明，gpcr可能是一个误称，因为许多7TM受体也通过非g蛋白偶联反应激活细胞过程，主要是通过蛋白质阻滞蛋白。对于5-HT2CR， G蛋白与阻滞蛋白介导的信号传导的相对作用尚不清楚。在人类中发现的snp，可以导致蛋白质序列的变化，在某些情况下，改变活性，可以提供对蛋白质关键结构-功能关系的见解。尽管在人类5-HT2CR中已经发现了超过2000个snp，但对这些snp的结构和功能后果的描述很少，也没有研究探讨这种受体结构的变化是否会通过G蛋白偶联或阻滞蛋白介导的途径改变优先信号传导。

The goal of this project at Fisk University is to identify novel signaling pathways that may be used by the serotonin (5-hydroxytryptamine; 5-HT) receptor which are revealed by examining subtly modified receptor structures, such as those encoded by single nucleotide polymorphisms (SNPs) found in human individuals. The objectives of the proposed research are to introduce into heterologous cells cDNAs encoding natural occurring polymorphic 5-HT2CRs whose sequence modifications are in regions previously identified as critical for coupling to G protein-mediated signaling pathways, and to characterize the functional consequences of these SNP-encoded sequence modifications. At least two undergraduate students per year will be involved in the research. Furthermore, master?s students in the lab will serve as role models for the undergraduates.The project will study the functional consequences of single nucleotide polymorphisms (SNPs) in the serotonin (5-HT) 2C receptor. 5-HT is a neurotransmitter that modulates a variety of neurophysiological responses by binding to one of 14 different receptor subtypes, one of which is the 5-HT2C receptor (5-HT2CR). The 5-HT2CR is a seven-transmembrane (7TM) spanning, G protein-coupled receptor (GPCR) that is involved in neuronal excitability, spatial learning, and appetite. Recent studies reveal that GPCRs may be a misnomer since many 7TM Receptors also activate cellular processes via non-G protein-coupled responses, primarily via the protein arrestin. The relative contribution of G Protein versus arrestin-mediated signaling is not well understood for the 5-HT2CR. SNPs identified in humans, which can lead to changes in protein sequence and, in some cases, altered activities, can provide insights into critical structure-function relationships of a protein. Though over 2,000 SNPs have been identified in the human 5-HT2CR, little characterization of structural and functional consequences of those SNPs has occurred, and no studies have explored whether or not such changes in receptor structure modify the preferential signaling via G protein-coupled versus arrestin-mediated pathways.