Dopamine is a modified aromatic amino acid that is released from neurons in order to modulate motor function, cognition and mood. Dysfunctions of the dopamine system contribute to movement disorders like Parkinson’s, cognitive disorders like schizophrenia and mood disorders like depression.

Dopamine is released from neurons in a paracrine fashion and reuptake mechanisms are distributed. Thus, the dopaminergic system is designed so that dopamine can diffuses through the extracellular space and act at a distance on a large number of target cells. Low levels of dopamine are tonically present producing widespread effects. Dopamine can also produce rapid transient effects on nearby targets when it is released from bursting neurons.

We are testing the hypothesis that tonic low levels of dopamine stabilize neurons, circuits and states. The lab examines the actions of tonic nanomolar dopamine at molecular, cellular and circuit levels. Our recent findings suggest that tonic nanomolar dopamine can define the activity dependence of neuronal ion channels by adjusting their SUMOylation state, and this stabilizes specific features of cell and circuit output.

Small Ubiquitin-like Modifier (SUMO) is a peptide that can be post-translationally added to a target protein to regulate protein-protein interactions. SUMOylation can coordinately regulate many diverse cellular processes ranging from DNA repair in the nucleus to signal transduction at the plasma membrane, and it is essential for most organisms. If dopamine regulates SUMOylation of target proteins, then disrupting dopamine signaling could globally alter SUMOylation. This, in turn, could interrupt several essential cellular processes.

Multiple neurological disease states may be linked to aberrant SUMOylation. For example, normally SUMOylation of α-synuclein promotes a functional, soluble conformation of the protein, but deSUMOylation leads to α-synuclein aggregation and cytotoxicity, which are hallmarks of Parkinson’s Disease. Also, the parkin gene is frequently mutated in autosomal recessive Parkinson’s patients and SUMOylation regulates parkin localization. Our studies on how tonic nanomolar dopamine regulates SUMOylation may provide insights into how disruptions in dopamine signaling lead to neurological disorders.

We are currently examining three broad questions: 1. How does dopamine regulate SUMOylation? 2. How does SUMOylation adjust ion channel function? 3. Does dopamine stabilize a state by regulating the SUMOylation profile of the cellular proteome? We are using molecular and electrophysiological approaches on a small invertebrate circuit to understand how dopamine regulates neuronal ion channel SUMOylation. To study how SUMOylation alters ion channel function, cultured mammalian neurons and tissue culture cells overexpressing ion channels and SUMOylation enzymes are used in molecular, cellular and electrophysiological experiments. The third question is being investigated in collaboration with Dr. Lingjun Li’s lab at the University of Wisconsin. A quantitative mass spectrometry approach is being developed to define the SUMOylation state of the neuronal proteome and how it is influenced by tonic nanomolar dopamine.