title: Two distinct effects of PIP2 underlie auxiliary subunit-dependent modulation of Slo1 BK channels.
abstract: Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a critical role in modulating the function of numerous ion channels, including large-conductance Ca(2+)- and voltage-dependent K(+) (BK, Slo1) channels. Slo1 BK channel complexes include four pore-forming Slo1 (α) subunits as well as various regulatory auxiliary subunits (β and γ) that are expressed in different tissues. We examined the molecular and biophysical mechanisms underlying the effects of brain-derived PIP2 on human Slo1 BK channel complexes with different subunit compositions that were heterologously expressed in human embryonic kidney cells. PIP2 inhibited macroscopic currents through Slo1 channels without auxiliary subunits and through Slo1 + γ1 complexes. In contrast, PIP2 markedly increased macroscopic currents through Slo1 + β1 and Slo1 + β4 channel complexes and failed to alter macroscopic currents through Slo1 + β2 and Slo1 + β2 Δ2-19 channel complexes. Results obtained at various membrane potentials and divalent cation concentrations suggest that PIP2 promotes opening of the ion conduction gate in all channel types, regardless of the specific subunit composition. However, in the absence of β subunits positioned near the voltage-sensor domains (VSDs), as in Slo1 and probably Slo1 + γ1, PIP2 augments the negative surface charge on the cytoplasmic side of the membrane, thereby shifting the voltage dependence of VSD-mediated activation in the positive direction. When β1 or β4 subunits occupy the space surrounding the VSDs, only the stimulatory effect of PIP2 is evident. The subunit compositions of native Slo1 BK channels differ in various cell types; thus, PIP2 may exert distinct tissue- and divalent cation-dependent modulatory influences.
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104 yttian1983@gmail.com hoshi@hoshi.org.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena and Jena University Hospital, D-07745 Jena, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Ullrich
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena and Jena University Hospital, D-07745 Jena, Germany.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
authors.affiliation: Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Shangwei
authors.initials: S
authors.lastname: Hou
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104 yttian1983@gmail.com hoshi@hoshi.org.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hoshi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D015640:Ion Channel Gating; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011485:Protein Binding; D014981:Xenopus
chemical_list: C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D019269:Phosphatidylinositol 4,5-Diphosphate
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