Research Opportunities in the Division of Clinical Pharmacology

MOLECULAR PHARMACOLOGY

BRUCE R CONKLIN, M.D., Assistant Professor of Medicine, Cellular and Molecular Pharmacology

Rewiring Receptor and G Protein Signals in Vivo

G Proteins orchestrate the signals of over 200 different mammalian hormone receptors that control vital physiological processes, such as proliferation of stem cells, heart rate, and neurotransmission. To better understand the role of G protein signaling in vivo, we have devised new methods to selectively activate receptors and G proteins at precise times and locations in transgenic mice. Our three primary avenues of research are:

New Receptors: We have developed a receptor that should be unresponsive to the endogenous levels of natural hormones but still be activated by administration of synthetic small molecule drugs. This modified receptor is called a RASSL (Receptor Activated Solely by a Synthetic Ligand). The first RASSLs activate G_i signaling and effectively control heart rate (expected result with G_i signaling). In other tissues, RASSLs may provide control over cell proliferation, development, and neurohormonal responses.
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. Several different G protein-specific phenotypes have resulted, providing an alternative strategy for identifying the principal responses to G protein signals in vivo.
Signal Monitoring in Vivo: We are currently using DNA arrays that simultaneously monitor the gene expression levels for over 6500 mouse genes. Preliminary studies suggests that each G protein pathway has a unique pattern of gene expression.

SELECTED PUBLICATIONS:

Skarnes WC, von Melchner H, Wurst W, Hicks G, Nord AS, Cox T, Young SG, Ruiz P, Soriano P, Tessier-Lavigne M, Conklin BR, Stanford WL, Rossant J. A public gene trap resource for mouse functional genomics. Nat Genet, 36:543–544, 2004.
Segal MR, Dahlquist KD, Conklin, BR. Regression approaches for microarray data analysis. J Comput Biol, 10:961–980, 2003.
Zambon AC, McDearmon EL, Salomonis N, Vranizan K, Johansen K, Adey D, Takahashi JS, Schambelan M, Conklin BR. Time- and exercise-dependent gene regulation in human skeletal muscle. Genome Biol, 4:R61–R61.12, 2003.