The Covarrubias laboratory utilizes a multipronged approach to investigate voltage-gated ion channels responsible for active electrical signaling in the nervous system. The general areas of interest concern pain physiology, mechanisms of general anesthesia and drug discovery. We focus on the following questions: 1) How are specific voltage gated potassium channels implicated in the mechanisms of neuropathic pain? 2) How are voltage-gated sodium and potassium channels implicated in the mechanisms of general anesthesia? and 3) what is the mechanism of action of novel neuroactive compounds? To tackle these problems, we combine, electrophysiology, optogenetics, computational modeling, recombinant DNA methodology, protein biochemistry, photoaffinity labeling and confocal microscopy. Answering these fundamental questions will promote the development of more effective interventions to treat chronic pain, safer general anesthetics and new drugs to treat neurological and psychiatric disorders. Over the years, our efforts have been supported by grants from the National Institutes of Health (NINDS, NIAAA, NIGMS), Sidney Kimmel Medical College, Vickie and Jack Farber Family Foundation, Autifony Therapeutics, Ltd. and Innovate UK. Institutional, domestic, international and industrial collaborators make invaluable contributions to our work.
Dysregulation of the Kv3.4 potassium channel: implications in spinal cord injury-induced neuropathic pain
We are investigating function and dysfunction of the potassium channel Kv3.4, which is uniquely expressed in dorsal root ganglion (DRG) neurons. Spinal cord injury (SCI)—induced inhibition of the Kv3.4 current might contribute to the hyperexcitability that underlies SCI-induced pain sensitization. Using electrophysiological, optogenetic, cellular, molecular, behavioral and computational methodologies, we investigate 1) the signaling cascades that modulate expression and function of Kv3.4 channels in the DRG under physiological and pathological conditions and 2) how Kv3.4 channels might play a critical role regulating spike properties and excitatory synaptic transmission in the nociceptive pathway. The long-term goal of this work is two-fold: 1) elucidate the mechanisms of pain signaling, and 2) identify potential therapeutic targets to treat SCI-induced neuropathic pain. Recent publications listed below contain more information about this work.
Mechanisms of general anesthetic action on voltage-gated potassium and sodium channels
We are investigating the sites of direct general anesthetic action on the potassium channels Kv1.2 (rat) and K-Shaw (Drosophila), and the prokaryotic sodium channels NaChBac and NavMs. Mainly, we focus on the most commonly used general anesthetics, propofol (intravenous) and sevoflurane (inhalational). While sevoflurane potentiates the activity of these potassium channels and inhibits the activity of sodium channels, propofol more selectively inhibits sodium channels. Through a multi-institutional collaborative effort (domestic and international), we use state-of-the-art biophysical, biochemical and structural techniques, and computational approaches to elucidate how the binding of sevoflurane and propofol modulate gating of potassium and sodium channels. The long-term goal of these studies is to elucidate the site and mechanisms of action to facilitate the development of more effective and safer general anesthetics. Recent publications listed below contain more information about this work.
Electrophysiological and molecular investigations of novel neuroactive compounds acting on a subset of voltage-gated potassium channels
This project concerns a relatively new area of research supported by Autifony Therapeutics, Ltd (http://www.autifonytherapeutics.com/). In a collaboration with researchers in the UK, Italy and the US, we are investigating newly discovered compounds that act as selective gating modifiers of neuronal Kv3 potassium channels. Our role in this international endeavor is to elucidate the mechanisms of action of these compounds by employing electrophysiological and recombinant DNA methodologies. The long-term goal of this project is to develop a new class of specific drugs that might help treat hearing disorders, schizophrenia and Alzheimer’s disease.