The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

Research in my lab focuses on the functions of a family of GPCRs (adrenergic receptors) in two areas: heart and Alzheimer disease. GPCRs are nature's most versatile biological sensors. They conduct the majority of transmembrane responses to hormones and neurotransmitters, and mediate the senses of pressure, sight, smell, and taste. Adrenergic receptors, which transmit signals in both central and peripheral nerve systems, are one of the most extensively characterized subfamilies of GPCRs, and serve as a model system for understanding the structure, cell biology, and physiology of GPCRs. We are investigating adrenergic receptors using in vitro and in vivo systems to determine the structural and cellular basis for more complex functional properties that are only observed in differentiated cells.

We have utilized strains of knockout mice for three beta (β) adrenergic receptor subtypes. These mice have provided insight into the physiologic role of specific receptor subtypes in vivo. In animal heart, from studies of β adrenergic receptor knockout mice we found that β1 and β2 adrenergic receptors play unique roles in regulating cardiovascular function, and are associated with heart failure development. We are using neonatal myocytes, sympathetic ganglia neurons from β1/β2 adrenergic receptor double knockout mice as a differentiated expression system to study the structural and cellular basis for differences in the functional properties of these two receptors. Our studies suggest that functional differences between β1 and β2 adrenergic receptors are due to their localization on post-synaptic cardiac myocyte cell surface relative to synapse formation between sympathetic ganglia neurons and cardiac myocytes.  

In another project, we have found that amyloid Aβ peptide directly activates β adrenergic receptor in a purified system. Aβ directly activates β1 adrenergic receptor to induce cAMP accumulation in astrocytes. We are expanding this new and exciting project to find out the cellular and functional role of Aβ-induced β adrenergic receptor signaling in both glia and neuronal cells, and its role in pathogenesis of Alzheimer disease.

Our current research focuses on four different areas:

1. Characterize the signaling complexes associated with β1 and β2 adrenergic receptors in cardiac myocytes, and the structural basis for the association under distinct agonist simulation.

2. Regulation of cAMP/PKA pathways by receptor activation and phosphodiesterases. We will use live-imaging studies on the individual subcellular events (i.e., cAMP, PKA, and Ca 2+ signaling) during activation of the receptors, and their significance in myocyte contraction and myocyte apoptosis.

3. Adrenergic synaptic regulation of β1 and β2 adrenergic receptor cellular and signaling properties within the model system of co-culturing sympathetic neurons and cardiac myocytes. We will try to understand neuron/muscular synaptic formation, and its influence on the adrenergic receptor function.

4. Adrenergic receptor signaling in Alzheimer disease. We are going to examine the receptor signaling induced by amyloid Aβ peptide in glia and neurons. We will try to determine whether the receptor signaling is involved the disease progress.

These studies will help us understand the signaling properties of the receptors at cellular levels, and may provide new approaches to intervene in the receptor functions in a variety of clinical conditions such as heart failure and hypertension, as well as Alzheimer disease.