Dr. Masami Yoshimura
Comparative Biomedical Sciences (CBS)
Cyclic AMP (cAMP), a ubiquitous second messenger in eukaryotic cells, plays a regulatory role in diverse biological processes including sugar and lipid metabolism, cell growth and differentiation, cardiac contractility, olfaction, as well as learning and memory. cAMP generation is controlled by a variety of hormones, neurotransmitters, and other extracellular molecules. This second messenger directly activates diverse molecules including protein kinase A, cyclic nucleotide-gated channels, and Epac, a guanine nucleotide exchange factor for the Ras-like small GTPase Rap1 and Rap2. The common form of signal transduction system that generates cAMP is a membrane-bound multi-component system. This system consists of various G protein-coupled receptors (GPCRs) which recognize extracellular signals, heterotrimeric G proteins, and membrane-bound adenylyl cyclase (AC), the enzyme that converts ATP to cAMP. Synthesis of cAMP by AC is a major determinant of the intracellular concentration of cAMP. Mammals, including humans, have nine different membrane-bound AC isoforms, type 1 to type 9 (AC1-AC9), and one soluble AC isoform (sAC). Each AC isoform has a distinct regulatory profile and tissue distribution. The activity of each isoform is controlled quite differently by a variety of factors. Regulation of a given AC isoform by multiple stimuli allows that isoform to function as a specific integrator of the external stimuli and further allows that isoform to play an interpretive role in signal transduction. AC isoforms could be important targets for a new generation of tissue- and cell-specific drugs or therapeutic interventions against various health problems.
I have been interested in how each isoform of AC is regulated by endogenous and exogenous factors. I started my research in the field of cAMP signal transduction by cloning mammalian AC cDNAs and genes. Our research found that drinking alcohol (ethanol) enhances the activity of AC in an isoform-specific manner and that AC7 is most ethanol responsive. We have studied the mechanisms responsible for this isoform-specific regulation. Now we shift our research focus to study the role of AC7 in the effect of alcohol drinking on the pathophysiology of live animals. Alcohol use increases the incidence of pneumonias and other infections caused by bacteria and viruses, and can negatively affect recovery from infections and traumatic injuries. Because of AC7’s high ethanol responsiveness and its high expression in immune cells, we hypothesize that AC7 is a primary factor that controls ethanol’s effects on immune responses. Currently, we study innate immune responses of the lung as a model to determine the role of AC7 in the effects of alcohol drinking. We use genetically modified mice and cell lines as model systems. Research methods employed include qRT-PCR, ELIZA, FRET analysis, RNAScope, flow cytometry, and functional analyses of macrophages such as phagocytosis, chemotaxis, nitric oxide generation, and bactericidal activity.