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

菲斯克大学的这个项目的目标是确定可能被5-羟色胺（5-羟色胺; 5-HT）受体使用的新的信号通路，通过检查微妙修饰的受体结构来揭示这些通路，例如在人类个体中发现的单核苷酸多态性（SNP）编码的通路。拟议研究的目标是将编码天然存在的多态性5-HT 2CR的cDNA引入异源细胞，这些多态性5-HT 2CR的序列修饰位于之前确定为与G蛋白介导的信号通路偶联的关键区域，并表征这些SNP编码的功能后果序列修饰。每年至少有两名本科生参与研究。而且，师父？本项目将研究5-羟色胺（5-HT）2C受体单核苷酸多态性（SNPs）的功能后果。5-HT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各种神经生理反应，其中一种是5-HT 2C受体（5-HT 2CR）。5-HT 2CR是一种七跨膜（7 TM）跨膜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可能是一个用词不当，因为许多7 TM受体也通过非G蛋白偶联反应激活细胞过程，主要是通过蛋白抑制蛋白。对于5-HT 2CR，G蛋白相对于抑制蛋白介导的信号传导的相对贡献尚不清楚。在人类中发现的SNP可以导致蛋白质序列的变化，并且在某些情况下，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5-HT 2CR中已经鉴定了超过2，000个SNP，但是对这些SNP的结构和功能结果的表征很少，并且没有研究探索受体结构中的这种变化是否通过G蛋白偶联途径与抑制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.