Reflecting long-standing interests in the relationship between potassium (K+) channel function and neurological disease and dysfunction, the overall research direction of my laboratory is aimed at the therapeutic targeting of K+ channels in multiple sclerosis (MS). Our research program includes studies related to the symptomatic treatment of neurological deficits and to immunomodulatory therapy for treating neuroinflammation and neurodegeneration in MS.
Studies investigating the structure-function relationships of drug/toxin-channel interactions are focused on the biophysical and molecular interactions of such compounds in voltage-gated K+ channels (Kv). Included are investigations of 4-aminopyridine (4-AP) and analogues of 4-AP in our cloned human brain Kv14 and mutant Kv1.4 channels, as well as various venom-derived peptide toxins in Kv1.1, Kv1.2 and Kv1.3 channels. Specific contributions of significance include: 1) delineation of the role played by rapid or N-type inactivation in determining the sensitivity of rapidly inactivating Kv channels to blockade by 4-AP; and 2) demonstration that conservative amino acid substitutions in the leucine heptad repeat region of a Kv channel stabilize the channel closed state, along with evidence that, in part, the mechanism of 4-AP blockade in Kv channels involves enhancing closure of the activation gate.
Studies investigating K+ channels in dendritic cells (DCs), as potential therapeutic targets for suppressing T cell function in MS, are focused on determining the biophysical and immunological roles of Kir, Kv1.5 and Kv1.3 channels in DCs. To date, we have shown that only immature DCs have Kir, while maturing and fully matured DCs have Kv1.5 and Kv1.3 K+ channels, being the first to report the presence of Kir and Kv1.5 in DCs. Furthermore, in collaboration with Horea Rus, MD (UMAB) and Peter A. Calabresi, MD (JHMI), we have shown high expression of Kv1.5 and Kv1.3 K+ channels in those DCs infiltrating MS brain tissue, but not in those found in normal brain tissue, and that selective blockade of these channels inhibits DCs immune function.
Judge SIV, Bever CT, Jr. (2006). Potassium channel blockers in multiple sclerosis: Neuronal Kv channels and effects of symptomatic treatment. Pharmacology & Therapeutics. 111:224-259 [Invited review].
Mullen KM, Rozycka M, Rus H, Hu L, Cudrici C, Zafranskaia E, Graber J, Pennington MW, Johns DC, Judge SIV#, Calabresi PA (2006). Potassium channels Kv1.3 & Kv1.5 are functionally expressed on dendritic cells. Annals of Neurology. 60:118-127.
Judge SIV, Lee JM, Bever, Jr. CT, Hoffman PM (2006). Voltage-gated potassium channels in multiple sclerosis: Overview and new implications for treatment of CNS inflammation and degeneration. Journal of Rehabilitation Research & Development. 43:111-122 [Invited review].
Rus H, Pardo C, Hu L, Darrah E, Cudrici C, Niculescu T, Niculescu F, Mullen KM, Allie R, Gao L, Wulff H, Beeton C, Judge SIV, Kerr DA, Knaus H-G, Chandy KG, Calabresi PA (2005). The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. Proceedings of the National Academy of Sciences USA. 102:11094-11099.
M’Barek S, Lopez-Gonzalez I, Andreotti N, di Luccio E, Visan V, Grissmer S, Judge S, El Ayeb M, Darbon H, Rochat H, Sampieri F, Béraud E, Fajloun Z, De Waard M, Sabatier J-M (2003). A maurotoxin with constrained standard disulfide bridging – innovative strategy of chemical synthesis, pharmacology and docking on K+ channels. The Journal of Biological Chemistry. 278:31095-31104.
Judge SIV, Yeh JZ, Goolsby JE, Monteiro MJ, Bever CT (2002). Determinants of 4-aminopyridine sensitivity in a human brain Kv1.4 K+ channel: phenylalanine substitutions in leucine heptad repeat region stabilize channel closed state. Molecular Pharmacology. 61:913-920.
Judge SIV, Monteiro MJ, Bever CT (1999). Inactivation gating and 4-AP sensitivity in human brain Kv1.4 potassium channel. Brain Research. 831:43-54.
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