Manuel L. Covarrubias, MD, PhD
Professor, Department of Neuroscience
Vickie and Jack Farber Institute for Neuroscience
Contact
233 S. 10th Street
231 BLSB
Philadelphia, PA 19107
215-503-4340
215-503-4358 fax
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Manuel L. Covarrubias, MD, PhD
Professor, Department of Neuroscience
Vickie and Jack Farber Institute for Neuroscience
Research & Clinical Interests
Voltage-gated ion channels; Structure, Function, Regulation & Mechanisms
The main goal of my research is to shed light on the molecular mechanisms that control electrical signaling in the brain.
In particular, I am interested in voltage-gated potassium channels, which are directly responsible for the regulation of electrical activity in the nervous system of primitive organisms and humans. My laboratory applies state-of-the-art technology to investigate two specific areas.
Gating of a neuronal shock-absorber: Voltage-gated potassium channels (Kv4) absorb the nerve impulse as it attempts to propagate back into the dendrites of nerve cells. In this area, we are investigating the conformational changes that underlie gating of Kv4 channels. Our findings have shown that these channels employ novel mechanisms to autoregulate their activity and that specific accessory subunits, zinc and nitric oxide play critical roles. Current efforts are aimed at solving the molecular basis of these mechanisms.
General anesthetic sites in potassium channels: Alcohol and general anesthetics affect brain activity by interacting with a variety of neuronal ion channels. In another area, my laboratory investigates the structural basis of alcohol and general anesthetic action. By exploiting a neuronal potassium channel (Shaw-2) as a model system, we have determined that general anesthetic agents regulate function by a direct interaction with the channel's activation gate.
We are now focused on mapping the molecular determinants and interactions at the site of action in the channel protein. These investigations apply the following methodologies: patch-clamp electrophysiology; kinetic analysis and computer modeling; genetic engineering; substituted cysteine accessibility method; heterologous expression; protein biochemistry; primary neuronal culture; RT-PCR.
The outcome of our research will help neuroscientists to gain insights into the molecular basis of learning, memory, hyperexcitability disorders, general anesthesia and alcohol intoxication.
Education
PhD, Chemistry, National University of Mexico (1980)
MD, National University of Mexico
Publications
- The binding and mechanism of a positive allosteric modulator of Kv3 channels
- Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy
- A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction
- Fundamental Neurochemistry Review: The role of enteroendocrine cells in visceral pain
- Intestinal neuropod cell GUCY2C regulates visceral pain