James Drewett, Ph.D.

James G. Drewett, Ph.D., University of Minnesota.

Molecular pharmacology of guanylyl cyclase-linked receptors. NIH and NSF-funded research in the laboratory is focused on a family of enzymes called guanylyl cyclases. Soluble or cytosolic forms of this enzyme are activated by nitric oxide and carbon monoxide. Particulate or membrane-associated forms are stimulated by peptide hormones or heat-stable enterotoxins. Enzyme activation results in the conversion of GTP or cyclic GMP. The latter is clearly an important intracellular second messenger. However, the lack of inhibitors or antagonists to the guanylyl cyclase family has hindered an understanding of the importance of cyclic GMP in mediating specific cellular responses. The focus of the laboratory is to define the importance of catalytically active forms of guanylyl cyclase in mediating antihypertensive activities in the cardiovascular system including: vasodilation, inhibition of adrenergic (sympathetic) neurotransmission, and reductions in the synthesis of the salt-retaining hormone, aldosterone. To this end we are taking the unique approach of using virus-mediate heterologous expression, site-directed mutagenesis, and chimeric enzymes in combination with traditional and novel pharmacology.

Recent publications

DREWETT, J.G., FENDLY, B.M.,  GARBERS, D.L. and LOWE, D.G.: Natriuretic  peptide receptor-B (Guanylyl cyclase-B) mediates CNP relaxation of precontracted rat aorta.  J. Biol.  Chem. 270: 4668-4674, 1995.

OLSON, L.J., LOWE, D.G. and DREWETT, J.G.: Novel natriuretic peptide receptor/guanylyl cyclase A-selective agonist inhibits angiotensin II- and forskolin-evoked aldosterone synthesis in a human zone glomerulosa cell-line.  Mol. Pharmacol. 50: 430-435, 1996.

OLSON, L.J., KNYCH, E.T. JR., HERZIG, T.C. and DREWETT, J.G.: Selective soluble guanylyl cyclase inhibitor reverses nitric oxide-mediated relaxation.  Hypertension(Dallas)  29: 254-261, 1997.

HANKE, C.J., DREWETT, J.G., MYERS, C.R. and CAMPBELL, W.B.:  Nitric oxide inhibits aldosterone synthesis by a guanylyl cyclase-independent effect.  Endocrinology 139:  4053-4060, 1998.
 

OLSON, L.J., HO, B.Y., CASHDOLLAR, L.W. and DREWETT, J.G.: Functionally active catalytic domain is essential for guanylyl cyclase-linked receptor-mediated inhibition of aldosterone synthesis.  Mol. Pharmacol. 54:761-769, 1998.

KREKLAU, E.L., CARLSON, E.J. AND  DREWETT, J.G.: Nitric oxide inhibits human aldosteronogenesis without guanylyl cyclase stimulation. Molec. Cell. Endocri
 

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