Manuel Covarrubias, MD, PhD

Contact Dr. Covarrubias

900 Walnut Street, Suite 400

Philadelphia, PA 19107

(215) 503-4341
(215) 955-4949 fax

What Mechanisms Govern the Function and Regulation of Voltage-Gated Potassium Channels in the Brain?

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. Dipeptidyl-peptidase-like proteins cast in a new role: Enabling scorpion toxin block of A-type K+ channels
2. 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
3. Modeling-independent elucidation of inactivation pathways in recombinant and native A-type Kv channels
4. Novel activation of voltage-gated K+ channels by sevoflurane
5. Modulation of Kv3.4 channel N-type inactivation by protein kinase C shapes the action potential in dorsal root ganglion neurons
6. Molecular mapping of general anesthetic sites in a voltage-gated ion channel
7. Cortactin is required for N-cadherin regulation of Kv1.5 channel function
8. Mechanisms of closed-state inactivation in voltage-gated ion channels
9. Alcohol and anesthetic action at the gate of a voltage-dependent K+ channel
10. Molecular physiology and modulation of somatodendritic A-type potassium channels
11. Allosteric modulation of a neuronal K+ channel by 1-alkanols is linked to a key residue in the activation gate
12. Molecular features of an alcohol binding site in a neuronal potassium channel
13. The link between ion permeation and inactivation gating of Kv4 potassium channels
14. Remodelling inactivation gating of Kv4 channels by KChIP1, a small-molecular-weight calcium-binding protein
15. Elimination of fast inactivation in Kv4 A-type potassium channels by an auxiliary subunit domain
16. Kv4 channels exhibit modulation of closed-state inactivation in inside-out patches
17. Potent inhibition of the aortic smooth muscle maxi-K channel by clinical doses of ethanol
18. General anesthetic action at an internal protein site involving the S4- S5 cytoplasmic loop of a neuronal K+ channel
19. Inactivation gating of Kv4 potassium channels: Molecular interactions involving the inner vestibule of the pore
20. Injection of Xenopus oocytes with mRNA from cultured neurons induces new currents and susceptibility to the damaging action of ruthenium red

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