Molecular overlap in the regulation of SK channels by small molecules and phosphoinositides

Miao Zhang; Xuan-Yu Meng; Ji-Fang Zhang; Meng Cui; Diomedes E Logothetis

doi:10.1126/sciadv.1500008

Molecular overlap in the regulation of SK channels by small molecules and phosphoinositides

Sci Adv. 2015 Jun 3;1(6):e1500008. doi: 10.1126/sciadv.1500008.

Authors

Miao Zhang¹, Xuan-Yu Meng², Ji-Fang Zhang³, Meng Cui², Diomedes E Logothetis²

Affiliations

¹ 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.
² Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, 1101 East Marshall Street, Richmond, VA 23298, USA.
³ 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.

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 PIP₂ binding site induced by a small-molecule SK channel modulator, NS309, can effectively enhance the interaction between the protein and PIP₂ to potentiate channel activity. This novel modulation of PIP₂ sensitivity 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.

Abstract

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