The serotonin 5-HT1A receptor is an intrinsic membrane protein which transduces extracellular signals, generated from binding of serotonin, into second messengers active in the cell cytosol or plasma membrane. The signal transduction mechanism involves interactions with guanine nucleotide binding proteins, which in turn activate or inhibit various enzymes or ion channels. thus, this receptor is a member of the super-family of G protein-coupled receptors. The 5-HT1A receptor is pluripotent, coupling to multiple signal transduction pathways within a single cell. The study of this receptor and its functional regulation have been enhanced by the cloning of its cDNA and gene from human and rat, from its expression in various host cell lines, and from the development of specific and potent antibodies raised against peptide fragments derived from the receptor. In the current proposal, two main areas will be addressed. The first involves the rapid desensitization of receptor-linked signal transduction pathways after brief exposure to serotonin or activators of protein kinase A or protein kinase C. The second involves the issue of which components of the signal transduction cascade confer specificity to the pluripotent linkages of this receptor. The importance of these studies can be addressed at both a mechanistic and a clinical level. The issue of specificity of signal transduction linkages of G protein-coupled receptors is central to an understanding of hormonal targeting. Because the 5-HT1A receptor couples to multiple signal transduction pathways, it serves as a useful paradigm for studying this issue. From a clinical perspective, the 5-HT1A may be important in the regulation of mood, temperature, immune function and blood pressure. For example, serotonin may influence blood pressure through several mechanisms including inhibition of central vasomotor loci, inhibition of norepinephrine release from post-ganglionic sympathetic neurons, release of endogenous vasodilators, or direct alteration of vascular tone. Therefore, the 5-HT1A receptor serves as a useful specific paradigm for receptors with clinical relevance regarding cardiovascular function, and also a general paradigm for studying the molecular mechanisms of pluripotent G protein- coupled receptors. The current proposal will utilize transfected cell models and various techniques derived from the fields of cell and molecular biology, biochemistry, and pharmacology to address two aspects of 5-HT1A receptor function at the molecular level: (i) mechanisms of pluripotent coupling to signaling systems, and (ii) mechanisms of receptor desensitization.
Showing the most recent 10 out of 21 publications
