Fields of Research

• Drug Discovery & Precision Medicine
• Intracellular Signaling
• Molecular Basis of Disease

Research Summary

Phosphodiesterases (PDEs) are enzymes that regulate the amplitude and duration of the second messenger molecules cAMP and cGMP. Many PDEs were intially discovered and studied in the Beavo laboratory, and many signaling agents that regulate PDEs were discovered by the Beavo lab and include insulin, glucagon, EDRF and many neurotransmitters. Much of the Beavo’s lab work focused on determining the physiological reasons for the existence of so many isozymes and to understand mechanistically how they function.

Research Statement

Many hormones, drugs and other agents modify physiological processes by causing changes in cAMP and cGMP. The amplitude and duration of these second messenger signals are controlled in large part by the activity of the specific cyclic nucleotide phosphodiesterases (PDEs) that control their degradation. The signaling pathways regulated by PDEs include such well known processes as visual transduction and male erectile function. They also include less well known pathways such as regulation of aldosterone by atrial natriuretic peptide and regulation of platelet aggregation by endothelial relaxation factor. Drugs that selectively inhibit individual PDE isozymes have a wide variety of different effects on an animals suggesting specific roles for most of the different PDEs.

There are eleven related but unique gene families that code for different PDEs and that most of these families contain more than one gene. Furthermore, each gene product is differentially spliced in different tissues to yield different isozymes. A major focus of the Beavo laboratory was to determine the molecular nature for the normal control of these isoenzymes. Many of the projects involved approaches to determine which cell types contain what PDE isozyme, and how that particular PDE isozyme contributes to the phenotype of the cell. In addition, crystal structure of several of these isozymes were pursued to understand structure/function of PDEs. Several PDE isozymes are known to regulated by covalent modification, and studies to determine how and to what extent these types of regulation are important to the physiological functions of the cells in which the PDEs are expressed were conducted.

Awards and Honors

1976-1981 Established Investigator, American Heart Assoc.

1980-present American Society of Pharm. & Exp. Therapeutics (ASPET)

1979-1998 NIH, Physiological Chemistry, Biochemistry, Endocrinology, and Pharmacology Ad Hoc Study Section Member

1984-1986 American Heart Association Study Section Member

1984-1987 Editorial Board, Molec. & Cell. Endocrinology

1986-1990 Associate Editor, Molecular Pharmacology

1989-1994 Editorial Board, J. Biol. Chem.

1995-2000 Editorial Board, Pharmacological Reviews

1993-1999 Program Committee, ASPET

1999-2005 Editorial Board PNAS

2000- 2009 Councilor, ASPET

2008- 2009 President, ASPET

1996-present Member National Academy of Sciences