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
2013, 2014 Endowment for Basic Sciences Teaching Award, University of Michigan Medical School
2004 Outstanding Faculty Service Award, Neuroscience Program
1999 Research Scientist Recognition Award
1992 Faculty Recognition Award
1986-1988 Basil O'Connor Research Scholar Award, March of Dimes
Rapid Generation of Human Genetic Loss-of-Function iPSC Lines by Simultaneous Reprogramming and Gene Editing.
Tidball AM, Dang LT, Glenn TW, Kilbane EG, Klarr DJ, Margolis JL, Uhler MD, Parent JM.
Stem Cell Reports. 2017; 9: 725-731
HIF2α Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response Independent of Insulin Signaling.
Ramakrishnan SK, Zhang H, Takahashi S, Centofanti B, Periyasamy S, Weisz K, Chen Z, Uhler MD, Rui L, Gonzalez FJ, Shah YM.
Cell Metab. 2016; 23: 505-16.
Transcriptional regulatory events initiated by Ascl1 and Neurog2 during neuronal differentiation of P19 embryonic carcinoma cells.
Huang HS, Redmond TM, Kubish GM, Gupta S, Thompson RC, Turner DL, Uhler MD.
J Mol Neurosci. 2015; 55: 684-705.
Negative regulation of Yap during neuronal differentiation.
Zhang H, Deo M, Thompson RC, Uhler MD, Turner DL.
Dev Biol. 2012; 361: 103-15.
Ascl1-induced neuronal differentiation of P19 cells requires expression of a specific inhibitor protein of cyclic AMP-dependent protein kinase.
Huang HS, Turner DL, Thompson RC, Uhler MD.
J Neurochem. 2012; 120: 667-83.
A novel fluorescent transcriptional reporter for cell-based microarray assays.
Redmond TM, Uhler MD.
Methods Mol Biol. 2011; 706: 41-52.
For a list of publications from Pubmed, click HERE