Autoreactive effector memory (TEM) T lymphocytes are implicated in the pathogenesis of multiple sclerosis (MS), type-1 diabetes mellitus (DM), psoriasis, rheumatoid arthritis and chronic graft-versus-host disease. Recent studies by our group suggest that the voltage-gated Kv1.3 channel is an exciting new target for the therapeutic manipulation of TEM cells. Kv1.3-based therapy for autoimmune disease that target TEM cells would have an advantage over broad and indiscriminate immunosuppression because naive/TCM cells would escape inhibition through up-regulation of the calcium-activated IKCal channel, leaving the bulk of the immune response unimpaired. In this proposal, we combine studies on patients with MS and type-1 DM with experiments in an animal model of MS, to establish the intellectual framework for the development of Kv1.3 as a therapeutic and diagnostic target for T cell-mediated autoimmune diseases.
Aim -1 determines if the presence of myelin-specific Kv 1.3high TEM cells in patients with MS is an indicator of disease activity and whether these cells decrease after therapy. We will also screen postmortem brain sections from MS patients for Kv1.3high activated TEM cells to support a role for these cells in pathogenesis.
Aim 2 evaluates the therapeutic effectiveness of Kv 1.3 and IKCa1 blockers in a rat model of MS that exhibits a chronic relapsing-remitting clinical course similar to MS.
Aim 2. 1 will investigate the channel and cell surface phenotype of T cells infiltrating the CNS during the initial and relapsing phases of disease and identify Kv1.3high TEM cells in inflammatory lesions in the CNS.
Aim 2. 2 will determine if ShK, the most potent Kv1.3 inhibitor, and TRAM-34, a specific IKCa1 inhibitor, administered alone or in combination, prevent and cure EAE. A successful outcome would pave the way to future trials in primate models of MS and eventually in humans.
Aim 3 examines whether insulin- and GAD65-specific memory T cells that are implicated in disease pathogenesis of type-1 diabetes mellitus, express the Kv1.3high activated TEM phenotype. Functional studies will ascertain whether ShK suppresses antigen-driven proliferation and cytokine production by these cells. If proven true, it would raise the possibility of using a channel-based therapy to ameliorate autoimmune disorders that afflict several million people globally.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Biophysics of Synapses, Channels, and Transporters Study Section (BSCT)
Program Officer
Stewart, Randall R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Schools of Medicine
United States
Zip Code
Galea, Charles A; Nguyen, Hai M; George Chandy, K et al. (2014) Domain structure and function of matrix metalloprotease 23 (MMP23): role in potassium channel trafficking. Cell Mol Life Sci 71:1191-210
Upadhyay, Sanjeev Kumar; Eckel-Mahan, Kristin L; Mirbolooki, M Reza et al. (2013) Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance. Proc Natl Acad Sci U S A 110:E2239-48
Nguyen, Hai M; Galea, Charles A; Schmunk, Galina et al. (2013) Intracellular trafficking of the KV1.3 potassium channel is regulated by the prodomain of a matrix metalloprotease. J Biol Chem 288:6451-64
Lioudyno, Maria I; Birch, Alexandra M; Tanaka, Brian S et al. (2013) Shaker-related potassium channels in the central medial nucleus of the thalamus are important molecular targets for arousal suppression by volatile general anesthetics. J Neurosci 33:16310-22
Nguyen, Hai M; Miyazaki, Haruko; Hoshi, Naoto et al. (2012) Modulation of voltage-gated K+ channels by the sodium channel ?1 subunit. Proc Natl Acad Sci U S A 109:18577-82
Chi, Victor; Pennington, Michael W; Norton, Raymond S et al. (2012) Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases. Toxicon 59:529-46
Tarcha, Eric J; Chi, Victor; Munoz-Elias, Ernesto J et al. (2012) Durable pharmacological responses from the peptide ShK-186, a specific Kv1.3 channel inhibitor that suppresses T cell mediators of autoimmune disease. J Pharmacol Exp Ther 342:642-53
Garcia, Adriana; Mirbolooki, Mohammad Reza; Constantinescu, Cristian et al. (2011) 18F-Fallypride PET of pancreatic islets: in vitro and in vivo rodent studies. J Nucl Med 52:1125-32
Rangaraju, Srikant; Khoo, Keith K; Feng, Zhi-Ping et al. (2010) Potassium channel modulation by a toxin domain in matrix metalloprotease 23. J Biol Chem 285:9124-36
Pennington, M W; Beeton, C; Galea, C A et al. (2009) Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes. Mol Pharmacol 75:762-73

Showing the most recent 10 out of 18 publications