title: Disruption of Kv1.1 N-type inactivation by novel small molecule inhibitors (disinactivators).
abstract: Kv1.1 channels are expressed in many regions of the brain and spinal cord [Monaghan, M. M.; Trimmer, J. S.; Rhodes, K. J. J. Neurosci.2001, 21, 5973; Rasband, M. N.; Trimmer, J. S. J. Comp. Neurol.2001, 429, 166; Trimmer, J. S.; Rhodes, K. J. Ann. Rev. Physiol.2004, 66, 477]. When expressed alone, they produce a delayed rectifier slowly inactivating type current that contributes to hyperpolarizing the neuron following depolarization. In the hippocampus Kv1.1 is co-expressed with Kvbeta1 (and other beta subunits), which converts Kv1.1 into a transient, fast inactivating current, reducing its ability to hyperpolarize the cell and thus increasing neuronal excitability. To reduce neuronal excitability, screening for compounds that prevent inactivation of Kv1.1 channels by Kvbeta1 was performed using a yeast two-hybrid screen. A variety of compounds were discovered in this assay and subsequently determined to disrupt inactivation of the ionic currents, and hence were termed 'disinactivators'. Several of these disinactivators also inhibited pentylenetetrazole-induced seizures (PTZ) in mice. Compounds were found to act by several mechanisms to prevent Kvbeta1 inactivation of Kv1.1 channels, including enhancement of Ca(2+) release/influx and by direct mechanisms. Two structural classes were identified that act on a Kvbeta1N70-Kv1.1 chimera where the N-terminal 70 amino acids of Kvbeta1 were attached to the N-terminus of Kv1.1. It is likely that these disinactivators act directly on the Kvbeta1 N-terminus or its receptor site on Kv1.1, thus preventing it from blocking Kv1.1 channels. Compounds acting by this mechanism may be useful for reducing neuronal hyperexcitability in diseases such as epilepsy and neuropathic pain.
authors.affiliation: Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.forename: Joseph
authors.initials: J
authors.lastname: Peevey
authors.forename: Flora
authors.initials: F
authors.lastname: Jow
authors.forename: Michael M
authors.initials: MM
authors.lastname: Monaghan
authors.forename: Grace
authors.initials: G
authors.lastname: Mendoza
authors.forename: Howard
authors.initials: H
authors.lastname: Zhang
authors.forename: Jerome
authors.initials: J
authors.lastname: Wu
authors.forename: Callain Y
authors.initials: CY
authors.lastname: Kim
authors.forename: James
authors.initials: J
authors.lastname: Bicksler
authors.forename: Lynn
authors.initials: L
authors.lastname: Greenblatt
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Lin
authors.forename: Wayne
authors.initials: W
authors.lastname: Childers
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bowlby
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D051662:Kv1.1 Potassium Channel / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009930:Organic Chemicals / Q000494:pharmacology*; D012640:Seizures / Q000517:prevention & control; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D020798:Two-Hybrid System Techniques
chemical_list: D009930:Organic Chemicals; D054852:Small Molecule Libraries; D051662:Kv1.1 Potassium Channel; D002118:Calcium