title: Molecular overlap in the regulation of SK channels by small molecules and phosphoinositides.
abstract: Phosphatidylinositol 4,5-bisphosphate (PIP2) directly interacts with the small-conductance Ca2+-activated K+2-a (SK2-a) channel/calmodulin complex, serving as a critical element in the regulation of channel activity. We report that changes of protein conformation in close proximity to the PIP2binding site induced by a small-molecule SK channel modulator, NS309, can effectively enhance the interaction between the protein and PIP2to potentiate channel activity. This novel modulation of PIP2sensitivity by small-molecule drugs is likely not to be limited in its application to SK channels, representing an intriguing strategy to develop drugs controlling the activity of the large number of PIP2-dependent proteins.
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, 1101 East Marshall Street, Richmond, VA 23298, USA ; Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, 9401 Jeronimo Road, Irvine, CA 92618, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, 1101 East Marshall Street, Richmond, VA 23298, USA.
authors.forename: Xuan-Yu
authors.initials: XY
authors.lastname: Meng
authors.affiliation: Department of Molecular Physiology and Biophysics, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA ; Farber Institute for Neurosciences and Graduate Program in Neuroscience, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
authors.forename: Ji-Fang
authors.initials: JF
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, 1101 East Marshall Street, Richmond, VA 23298, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Cui
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, 1101 East Marshall Street, Richmond, VA 23298, USA.
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis