Molecular Pharmacology and Genetics of Adrenergic Receptors
Our laboratory combines molecular pharmacology approaches with translational human functional genomics. The theme unifying current projects is that reproducible perioperative stress represents a unique paradigm for understanding the effects of acute and chronic stress. The laboratory is involved in studying mechanisms underlying regulation of adrenergic receptors (ARs) in health and disease, primarily focusing on regulation of alpha1ARs. Since these receptors are important in smooth muscle and the heart, diseases such as hypertension and myocardial hypertrophy, as well as growth responses, are our main foci. Three alpha1AR subtypes exist (alpha1a, alpha1b, alpha1d); over the years we have been involved in cloning cDNAs encoding each of these subtypes from both animal and human sources (PNAS, 1988; 85:7159; J Biol Chem, 1990; 265:8183; J Biol Chem, 1991; 266:6365; JPET, 1995; 272:134; J Urol, 2002; 167:1513) and demonstrating that alpha1aARs are present and functional in human vasculature (particularly resistance vessels and coronary arteries) and modified by age (Circulation, 1999; 100: 2336-2343) as well as other human tissues (Neuroscience 2005; 135: 507-523).
In order to understand mechanisms underlying these changes, our laboratory is currently examining regulation of the human alpha1aAR at transcriptional and protein levels (J Biol Chem, 2002; 277:9570; J Biol Chem, 1997; 272:28237; Nature 2006 AfCS-Nature Molecule Page, FASEB 2007; in press) in the presence and absence of hypoxia (J Biol Chem, 2003; 278: 8693). Within this context, we are pursuing an emerging line of investigation that may play a key role in the uniqueness of the alpha1aAR in continued signaling in the presence of agonist in situations where alpha1b and alpha1dARs (and indeed many G protein-coupled receptors [GPCRs]) concurrently dampen (desensitize and/or downregulate) signaling. Our laboratory has demonstrated that the alpha1aAR, but not the alpha1bAR, undergoes constitutive internalization in the absence of agonist, suggesting internalization of alpha1aARs may use alternative trafficking pathways (Mol Pharmacol, 2004; 66:843). Recent data suggest this may be due to compartmentalization of the alpha1aAR to lipid enriched regions of the plasma membrane termed lipid rafts, thereby restricting coupling of the receptor to distinct subsets of intracellular signaling molecules. Finally, we utilize the power of chromatin immunoprecipitation and microarray analysis to extend these studies to elucidate dynamic transcriptional mechanisms that reprogram in cellular gene expression (J Biol Chem, 2005; 280:31368).
A recent emphasis in the laboratory is studying the role of genetic variability on human cardiovascular disease. Specifically the role of naturally occurring single nucleotide polymorphisms (SNPs) and insertions/deletions of alpha1-adrenergic receptor signaling is being investigated (Naunyn Schmiedeberg's Arch Pharmacol 2005; 371: 229-239). These studies utilize classical genetic approaches; large scale genomic sequencing, SNP identification, and analysis for association with disease in highly phenotyped populations, as well the biology of each SNP in terms of alpha1AR signal transduction pathways. In addition, the Schwinn laboratory is actively involved in the Perioperative Genomics project, a group studying how genetics variability can be used to predict (and intervene to prevent) adverse outcomes in the perioperative period. Several key publications have resulted from these studies and new mechanistic approaches at cellular/tissue/animal levels are being added (J Am Coll Cardiol 2005; 46: 1965-77, Circulation 2006; 114: 275-281; J Am Coll Cardiol 2007; in press).
A broad spectrum of individuals interact and study in our laboratory (undergraduates, medical students, graduate students, postdoctoral fellows, junior faculty, various collaborators), and wide-ranging approaches are utilized (e.g., molecular biology, classical pharmacology, biochemistry, pharmacogenetics, microarrays, proteomics, metabolomics, statistical genetics, and clinical trials). The goal of our laboratory is to examine clinically important questions using basic science approaches, with a final goal of taking answers back to the clinic--true translational medicine.