Bruce R.
Conklin, M.D.
Assistant Professor,
Dept. of Medicine and Cellular
and Molecular Pharmacology, UCSF; Investigator at the Gladstone Institute of Cardiovascular Disease, SFGH

Contact Information:
bconklin@gladstone.ucsf.edu
Tel: (415) 695-3758
Fax: (415) 285-5632
Box 1230, SFGH 40, 301

Links:
Lab Page
GenMapp
PIBS
Biomedical Sciences

Publications

We are interested in how G protein coupled receptors (GPCRs) control electrically active tissues. In tissues such as the heart and the brain, GPCRs orchestrate the intracellular biochemical signals with the actions of ion channels at the cell surface. Prolonged signaling results in changes in gene expression, new levels of responsiveness and occasionally pathological states. To best understand this process we have devised several new methods to control G protein signals in vivo and use new techniques to monitor signaling events on a genomic level.

Our three primary avenues of research are:
1. New Receptors: using engineered receptors and G proteins. To take control of signaling at the receptor level, we have engineered versions of the kappa opioid receptor (KOR) to be unresponsive to the endogenous levels of natural hormones but still be activated by administration of synthetic small molecule drugs. These modified receptors are called a RASSLs (Receptor Activated Solely by a Synthetic Ligand) and have been extensively studied in tissue culture cells (Coward et al 1998). When these KOR-based RASSLs are expressed in the heart, they will activate Gi signaling and as expected, can dramatically slow heart rate (Redfern et al, 1999). When these RASSLs are vastly over expressed that in the heart the mice develop a lethal cardiomyopathy (see Mouse Picts, 1999).

2. Constitutively Active G Proteins: We have expressed constitutively active versions of G proteins under the temporal-spatial control of the tetracycline transactivator system in mice (see Tet system). Several different G protein-specific phenotypes have resulted, providing an alternative strategy for identifying the principal responses to G protein signals in vivo.

3. Signal Monitoring in Vivo: We are currently using DNA arrays that simultaneously monitor the gene expression levels for over 11,000 mouse genes. Preliminary studies suggests that each G protein pathway has a unique pattern of gene expression
(See DNA-arrays).