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Potassium Channel Physiology

Jerod S. Denton
Assistant Professor of Anesthesiology
Assistant Professor of Pharmacology
615-343-7385 (office)
jerod.s.denton@vanderbilt.edu

1. High-throughput discovery of novel potassium channel probes
Inward rectifying K+ (Kir) channels play key roles in cardiac, neuronal, endocrine and epithelial physiology and disease. Progress in the field has been hampered by the lack of selective pharmacological probes that target specific members of the Kir channel family. To overcome this barrier, we recently performed a high-throughput screen of approximately 250,000 organic small molecules to discover novel modulators of Kir1.1, the founding member of the Kir channel family. We are working closely with researchers in the Vanderbilt Institute for Chemical Biology to understand how these newly discovered compounds modulate Kir channel function. Students interested in combining chemistry, pharmacology and electrophysiology to understand K+ channel structure-function relationships are strongly encouraged to apply.

NOTE TO ROTATION STUDENTS: Students interested in working on this project will have a unique opportunity to use state-of-the-art automated (Port-a-Patch) and fully automated (Patchliner) patch clamp electrophysiology workstations from Nanion Technologies (http://www.nanion.de). These automated patch clamp rigs require very little training, so students can spend their rotation studying ion channels, not learning how to patch clamp a cell.

2. Potassium channel structure, function and trafficking in human disease
Heritable mutations in the gene encoding Kir1.1 give rise to antenatal Bartter syndrome (aBs), kidney tubule disease presenting with renal salt and water wasting and acid-base disturbances. More than 30 loss-of-function mutations distributed throughout the channel protein have been identified; however, surprisingly little is known about the molecular and cellular mechanisms underlying channel dysfunction for most of these mutations. We are using a combination of molecular modeling, novel computational methods, mutagenesis, protein biochemistry and patch clamp electrophysiology to understand how mutations disrupt Kir1.1 channel function and trafficking in aBs patients. We are also testing if novel channel activators discovered in high-throughput screening (see above) can rescue certain loss-of-function aBs mutations in Kir1.1.

For more information, please visit the lab website.

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