Research Overview: G Protein Signaling

Goals: Elucidate novel G protein signaling mechanisms in cardiovascular, neuronal or cancer cells. Toward this goal we are working to:

Significance: G protein signaling dysregulation causes 1) cardiovascular diseases including heart failure and hypertension; 2) nervous system disorders such as depression, schizophrenia and drug addiction; and 3) cancer. As new G protein signaling mechanisms are elucidated by basic research, novel disease mechanisms will be revealed and new therapeutics developed. Further background information about G protein signaling can be found at the STKE web site and GPCR database.

Current projects (also see page devoted to lab people):

Techniques:


Project Summaries

G protein signaling in hypertension: We have discovered a new genetic defect in a GPCR regulatory mechanism that causes hypertension in mice and has been linked to hypertension in humans. We have found that a G protein regulator called RGS2 is essential for blood pressure regulation because RGS2 knockout mice are strikingly hypertensive. Even RGS2-/+ mice exhibit elevated blood pressure. This is very exciting because it shows that RGS2 is a hypertension QTL (quantitative trait locus). We therefore are in a unique position to establish the mechanism by which a hypertension QTL regulates blood pressure, long a goal of the field. This has led us to find that RGS2 is an effector of the nitric oxide (NO)-cGMP pathway that promotes relaxation of the resistance vasculature. Thus, without RGS2 the resistance vasculature does not relax normally, providing one mechanism contributing to hypertension. This also is an important discovery because the NO field has long been searching for downstream effectors that mediate vascular relaxation and regulate blood pressure.

Transplantation studies have shown that RGS2 deficiency in kidney is sufficient to elevate blood pressure. We therefore are using cell type specific RGS2 knockout mice to determine which aspects of renal function are dysregulated by the absence of RGS2. We anticipate that these studies will reveal fundamentally new renal signaling mechanisms that play key roles in blood pressure regulation and hypertension. (Click here to return to the top of this page)

G protein signaling in the nervous system: This project focuses on the RGS7 family (RGS6, 7, 9 and 11) of G protein regulators in the nervous system. This family is fascinating because it regulates the action of addictive drugs, vision and postnatal development. Furthermore, it is likely to transduce unique signals by associating with a novel G protein beta subunit (Gbeta5). Accoridingly, to characterize new mechanistic functions of the RGS7 family and Gbeta5 we have begun to identify novel proteins that interact with these molecules. This led to our discovery of R7BP. R7BP is exciting because of its unanticipated ability to function as an intracellular shuttling protein that traffics RGS7/Gbeta5 complexes between the plasma membrane and nucleus. We have discovered that shutting is regulated by reversible palmitoylation/depalmitoylation of R7BP under the control of G protein signals. Thus, this process provides a novel mechanism for transmitting neuronal GPCR signals directly from the plasma membrane to the nucleus. Currently, we are working to understand how R7BP regulates the RGS7/Gbeta5 complex, and what R7BP does in the nucleus. In addition, we have generated R7BP knockout mice to determine which neuronal functions require this novel shuttling mechanism. We believe that these studies will reveal exciting new mechanisms that regulate neurotransmitter action, which are likely to be relevant to nervous system development, several neurological disorders and possibly drug addiction. (Click here to return to the top of this page)

Molecular imaging of G protein prenylation inhibitors in breast cancer: Many small G proteins such as Ras have critical role in breast cancer and many other maligancies. Several classes of drugs have been developed to inhibit these small G proteins by blocking the addition of lipid modifications (prenyl groups) that are required for plasma membrane association and tumor promotion. However, these G proteins also regulate curical processes in host tissues that are likely to impact tumor progression. Therefore, a key challenge in the field is to determine which tumor or host cell types are targeted by these drugs when administered at therapeutic doses in vivo. To answer this question we are developing a novel bioluminescence-based molecular imaging system that will enable us to detect prenylation inhibitor action toward any specific cell type of interest. (Click here to return to the top of this page)