Philadelphia University + Thomas Jefferson University

Covarrubias, Manuel

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Manuel L. Covarrubias, MD, PhD

Contact Dr. Covarrubias

900 Walnut Street
JHN 4th floor
Philadelphia, PA 19107

(215) 503-4340
(215) 503-4358 fax

Medical School

MD, National University of Mexico
PhD, National University of Mexico, Chemistry, 1980

Research & Clinical Interests

Voltage-gated ion channels; Structure, Function, Regulation and 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.

Publications

Most Recent Peer-Reviewed Publications

  1. Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K+ Channel Dysfunction in DRG Neurons
  2. Photoaffinity Ligand for the Inhalational Anesthetic Sevoflurane Allows Mechanistic Insight into Potassium Channel Modulation
  3. Sites and Functional Consequence of Alkylphenol Anesthetic Binding to Kv1.2 Channels
  4. A novel bifunctional alkylphenol anesthetic allows characterization of γ-aminobutyric acid, type A (GABAA), receptor subunit binding selectivity in synaptosomes
  5. Closed-state inactivation involving an internal gate in Kv4.1 channels modulates pore blockade by intracellular quaternary ammonium ions
  6. Mechanistic Insights into the Modulation of Voltage-Gated Ion Channels by Inhalational Anesthetics
  7. Positive allosteric modulation of Kv channels by sevoflurane: Insights into the structural basis of inhaled anesthetic action
  8. Role for the Propofol Hydroxyl in Anesthetic Protein Target Molecular Recognition
  9. Kv3.4 channel function and dysfunction in nociceptors
  10. Dysregulation of Kv3.4 channels in dorsal root ganglia following spinal cord injury
  11. Modulation of a voltage-gated Na+ channel by sevoflurane involves multiple sites and distinct mechanisms
  12. Dipeptidyl-peptidase-like proteins cast in a new role: Enabling scorpion toxin block of A-type K+ channels
  13. Insight into the modulation of Shaw2 Kv channels by general anesthetics: Structural and functional studies of S4-S5 linker and S6 C-terminal peptides in micelles by NMR
  14. Modeling-independent elucidation of inactivation pathways in recombinant and native A-type Kv channels
  15. Novel activation of voltage-gated K+ channels by sevoflurane
  16. Modulation of Kv3.4 channel N-type inactivation by protein kinase C shapes the action potential in dorsal root ganglion neurons
  17. Molecular mapping of general anesthetic sites in a voltage-gated ion channel
  18. Cortactin is required for N-cadherin regulation of Kv1.5 channel function
  19. Mechanisms of closed-state inactivation in voltage-gated ion channels
  20. Simulating complex ion channel kinetics with IonChannelLab.