Advance drug development efforts aimed at ameliorating a variety of central nervous disorders. 

• Fluorescent biosensor for ATP that can be applied to enzyme-linked assays, ischemia testing, diagnostic chemistry tests, or biosynthetic process control
• K_ATP channels as possible drug targets in epilepsy or other paroxysmal disorders

Dr. Yellen’s research is focused on two general areas: neuronal ion channels, and epilepsy. Both areas converge on neuronal potassium channels, a protein class that Dr. Yellen studies from both structural and functional perspectives. Because these proteins modulate ion movements and electrical signals across cell membranes, their gating properties help determine the signaling attributes of neurons. Dr. Yellen’s lab is elucidating the structural nature of their moving parts, which allow the channels to open and close, and often control the channels’ interactions with drugs.

Dr. Yellen is exploring the well-known, but poorly understood, phenomenon of dietary effects on epileptic seizures. He recently reported findings on the connection between a ketogenic diet and the activity of the ATP-sensitive potassium channel; these findings are opening up new avenues for epilepsy treatment. 

Dr. Yellen’s lab is also developing fluorescent biosensors that can determine the level of key cellular metabolites, including the ratio of ATP to ADP in a living cell or in a biochemical sample.
 

To study electrical signaling in the brain, Dr. Yellen employs genetic and biophysical methodologies to dissect the biochemical structural and functional relationships of membrane ion channels, including voltage-activated potassium channels. Key attributes of neuronal signaling derive from highly regulated channel gating. Dr. Yellen’s lab recently studied the hyperpolarization-activated cyclic nucleotide gated (HCN) cation channels, which are permeable to sodium and potassium ions, and can be activated by cyclic nucleotides. HCN channels involve cardiac electrical signaling, and are implicated in neuropathic pain. These studies focused on how voltage gates the HCN channels. The lab altered the structure of the channel within specific domains and found that during the gating process, two key channel regions are brought together, leading to a polarity reversal.

Dr. Yellen’s lab has also discovered important structural and functional relationships in the voltage-dependent, Shaker potassium channel that helps control the excitability of neurons. The lab discovered key regions of the voltage-dependent channel proteins that can act as gates to open and close the channel, and also that regulate the access of channel drugs to their binding sites. 

The lab has undertaken epilepsy studies to address the problems faced by the 1 to 2 percent of the population who have been diagnosed with this disease. The epilepsy studies have shed light on a longstanding, but unsubstantiated, observation: many epilepsy patients can control their seizures by adopting a ketogenic diet, that is, a low-carbohydrate, high-fat diet. Dr. Yellen’s research revealed that a ketogenic diet can stimulate the activity of the ATP-sensitive KATP channel and consequently curtail the neuronal firing rate. These findings suggest potential strategies for pharmacologic intervention.  
 

Biological Mechanisms and Pathways

• ATP-sensitive potassium channel •
• Electrical signaling •
• Ion channel •
• Ketogenic diet •
• Nervous system •
• Neuron •
• Pacemaker channel •
• Voltage-activated potassium channel •
• Voltage-gated ion channel
•  

Central Nervous System

• Epilepsy •
• Ketogenic diet
•  

Disease Mechanisms

• Epilepsy
•  

Research Tools and Instrumentation

• Biosensor •
• Genetically-encoded biosensor
•  

Therapeutics

• Anticonvulsant therapy
•