Research ArticlePHARMACOLOGY

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

Science Advances  10 Jul 2015:
Vol. 1, no. 6, e1500008
DOI: 10.1126/sciadv.1500008

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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.

Keywords
  • PIP2
  • SK2
  • NS309
  • small molecule
  • phosphoinositides
  • MD simulations

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