Areas of Interest
The research in our laboratory addresses the role of protein phosphorylation in the regulation of cell function, particularly the regulation of cells within the nervous system. The second messenger cyclic AMP (cAMP) and the protein kinase cAMP-dependent protein kinase have been shown to play key roles in the biochemical mechanisms which form the basis for learning and memory in invertebrate organisms. Our laboratory studies the role of cAMP and cAMP-dependent protein kinase in the regulation of neuronal gene transcription and ion channel function in the mammalian nervous system.
The protein kinase contains two regulatory and two catalytic subunits and the regulatory subunit inhibits the kinase activity of the catalytic subunit by occupying the substrate binding site. The binding of cAMP to the regulatory subunit releases the enzymatically active catalytic subunit to phosphorylate important neuronal proteins such as transcription factors and ion channels which then alter the function of the neuron. In mammals, multiple isoforms of both the regulatory and catalytic subunits lead to a complex mixture of cAMP-dependent protein kinases with slightly different biochemical properties within the nervous system.
One of the goals of our lab is to define the biochemical and cell biological properties of these enzyme isoforms and to correlate these properties with the multitude of distinct cellular responses seen in various neuronal cell types. Recently, a second major research focus has developed in the laboratory dealing with the closely related cyclic GMP-dependent protein kinase. Although functionally related to cAMP-dependent protein kinase, the cGMP-dependent protein kinase responds specifically to the second messenger cyclic GMP and does not consist of distinct regulatory and catalytic subunits. Instead, the cGMP-dependent protein kinase consists of a single polypeptide which contains both regulatory and catalytic domains. Although the cellular substrates for cGMP-dependent protein kinase are not well characterized, experimental evidence suggests that activation of the kinase causes a decrease in concentration of a key neuronal second messenger, calcium. Current studies are focusing on the multiple isoforms of cGMP-dependent protein kinase and the role that they play in the regulation of neuronal gene transcription and ion permeability.
The work in our laboratory is inherently multidisciplinary in nature and employs biochemical, molecular genetic, cell biological, and electrophysiological techniques. These studies often involve collaborations with other laboratories at Michigan or at other institutions.
Honors & Awards
1986-1988 March of Dimes Basil O'Conner Research Scholar
1992 Faculty Recognition Award
1999 Research Scientist Recognition Award
2004 Outstanding Faculty Service Award/Neuroscience Prog
Taylor, M. K., Ahmed, R., Begley, M. and Uhler, M.D. (2002) Autoinhibition and isoform-specific dominant negative inhibition of the type II cGMP-dependent protein kinase. J. Biol. Chem. 277(40): 37242-53. PMID: 12093798
Zhang, L., Duan, C.J., Li, G., Uhler, M.D., Logsdon, C.D. and Simeone, D.M. (2004) A Transforming Growth Factor beta-Induced SMAD3/SMAD4 Directly Activates Protein Kinase A. Mol. Cell Biol. 24:2169-80. PMID: 14966294
Redmond, T. M., Ren, X., Kubish, G., Atkins, S., Low, S. and Uhler, M.D. (2004) Microarray Transfection Analysis of Transcriptional Regulation by cAMP-dependent protein kinase. Mol. Cell. Proteomics. 38:770-9. PMID: 15118071
Leinninger, G. M., Backus, C., Uhler, M.D., Lentz, S. I. and Feldman, E. L. (2004) Phosphatidylinositol 3-kinase and Akt effectors mediate insulin-like growth factor-I neuroprotection in dorsal root ganglia neurons. FASEB J. 18(13): 1544-6. PMID: 15319368