Phospholipase C Biochemistry and Disease
Ribbon model of the 3-dimensional structure of phospholipase d with bound IP3.
One main area of research is on the biology and biochemistry of the enzymes that hydrolyse phosphatidyl inositol 4,5-bisphosphate to produce the crucial second messengers inositol 1,4,5 trisphosphate and diacylglycerol. This family of phosphatidylinositol specific phospholipase C enzymes consists of six classes of 11 enzymes that initiate the signal transduction cascade in response to cell surface receptor activation. Our laboratory focuses on understanding regulation of the phospholipases that are regulated directly by G proteins. Some of the general areas of research include:
1) Biochemical mechanism for regulation by G proteins which include:
Understanding the structural basis for recognition of PLC by G proteins.
Understanding mechanisms for activation whether allosteric or membrane recruitment.
Functional domain analysis. By cloning and expressing the different domains of the phospholipase, we can begin to understand the roles for these individual domains in the control of enzyme activity and signal transduction.
2) Roles for PLC in physiology and disease.
To understand specific physiological roles of phospholipase C in human disease we have used genetic deletion technology in mice to delete or express specific phospholipase C isoforms. These animal models provide valuable tools for understanding the roles of these enzymes both in physiology and pathophysiology. In particular, novel roles for PLC have been identified in cardiac function and disease as well as in diabetes. With these models in hand, specific therapeutic strategies can be tested to treat these and other diseases.
Alan V. Smrcka, Ph.D.
University of Rochester
School of Medicine and Dentistry
601 Elmwood Avenue
Rochester, NY 14642