Ion channels govern sensory transduction, fast electrical signaling and intercellular communication. It is, therefore, no surprise that ion channel dysfunction and dysregulation is associated with numerous congenital and acquired diseases generally known as channelopathies. This realization has stimulated the discovery of potentially therapeutic small molecule modulators that target ion channels. The Covarrubias Lab applies multidisciplinary team-driven approaches (patch-clamp electrophysiology, in-silico modeling, molecular biology, animal models, cryo-EM, MD simulation, etc.) to elucidate the structure, function, and modulation of voltage-gated potassium (Kv) and sodium (Nav) channels. The knowledge gained is necessary to understand mechanisms of function and dysfunction and develop therapeutic interventions.
By pursuing these interests at a fundamental level, we have discovered mechanisms of activation and inactivation with non-canonical features and their modulation by accessory subunits and second messenger molecules. Also, we have identified the sites and mechanisms of action of small molecule modulators of Kv and Nav channels (general anesthetics and positive allosteric modulators). Extending our interest to molecular pain physiology, the Covarrubias Lab has shed light on the ways in which the function and dysfunction of a specific Kv channel contribute to pain signaling and neuropathic pain, respectively. Ongoing work is investigating 1) the ionic basis of the modulation of excitable enteroendocrine cells in the small intestine (neuropod cells) by linaclotide, a drug currently used to treat irritable bowel syndrome, and 2) the role of dysregulated glutamatergic synaptic signaling in the spinal cord in the mechanism of neuropathic pain induced by spinal cord injury.
For more than three decades, the Covarrubias Lab has been supported by grants from the NIH (NINDS, NIGMS, NIAAA, and NIDDK), industry (Autifony Therapeutics, Ltd.) and intramural sources (Farber Discovery Fund, and SKMC Dean’s office).
