title: Selective phosphorylation modulates the PIP2 sensitivity of the CaM-SK channel complex.
abstract: Phosphatidylinositol bisphosphate (PIP2) regulates the activities of many membrane proteins, including ion channels, through direct interactions. However, the affinity of PIP2 is so high for some channel proteins that its physiological role as a modulator has been questioned. Here we show that PIP2 is a key cofactor for activation of small conductance Ca2+-activated potassium channels (SKs) by Ca(2+)-bound calmodulin (CaM). Removal of the endogenous PIP2 inhibits SKs. The PIP2-binding site resides at the interface of CaM and the SK C terminus. We further demonstrate that the affinity of PIP2 for its target proteins can be regulated by cellular signaling. Phosphorylation of CaM T79, located adjacent to the PIP2-binding site, by casein kinase 2 reduces the affinity of PIP2 for the CaM-SK channel complex by altering the dynamic interactions among amino acid residues surrounding the PIP2-binding site. This effect of CaM phosphorylation promotes greater channel inhibition by G protein-mediated hydrolysis of PIP2.
authors.affiliation: 1] Department of Molecular Physiology and Biophysics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. [2] Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Miao
authors.identifier: 000000023099155X
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Xuan-Yu
authors.initials: XY
authors.lastname: Meng
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Cui
authors.affiliation: Department of Biochemistry &Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Pascal
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
authors.affiliation: 1] Department of Molecular Physiology and Biophysics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. [2] Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. [3] Graduate Program in Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Ji-Fang
authors.initials: JF
authors.lastname: Zhang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000596:Amino Acids / Q000378:metabolism; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D047390:Casein Kinase II / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D018129:Phosphatidylinositol Phosphates / Q000494:pharmacology* / Q000502:physiology; D010766:Phosphorylation; D011487:Protein Conformation; D011493:Protein Kinase C / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors*
chemical_list: D000596:Amino Acids; C496897:KCNN2 protein, human; D018129:Phosphatidylinositol Phosphates; D051640:Small-Conductance Calcium-Activated Potassium Channels; C106336:phosphatidylinositol 3,5-diphosphate; D047390:Casein Kinase II; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D000109:Acetylcholine
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