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Phosphatidylinositol phosphate activates KCNMA1. 18 / 18
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"Moreover, the differential expression of BK accessory subunits across tissues raises the possibility that a direct PIP 2 modulation of BK channel function is specifically relevant in tissues where the beta 1 subunit is highly expressed."
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"At the functional level, and linked to the previous question, the gating processes that underlie PIP modulation of BK channel activity when evaluated under physiological voltage and Ca need to be pinpointed."
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"In the absence of Ca 2+ at very negative voltages where the VSDs are mostly at rest, PIP 2 increased P o in both Slo1 (XREF_FIG) and Slo1 + beta1 (XREF_FIG), and the fractional increases were indistinguishable between the two channel types (P = 0.955; XREF_FIG), despite the contrasting effects at more positive voltages where VSD activation and G/G max are appreciable."
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"Two distinct effects of PIP 2 underlie auxiliary subunit dependent modulation of Slo1 BK channels."
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"Recently, also two members of the family of high conductance K + channels, namely Slo1 (BK channels) and Slo3 channels have been shown to be activated by PIP 2 [10,11] ."
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"Third, PIP activation of BK channel positively correlated with the number of negative charges in the inositol ring; thus 1,2-dipalmitoyl phosphatidylinositol 3,4,5-trisphosphate (PIP ) (net charge ≥−4) demonstrated a higher potentiating efficacy than PIP (net charge ≥−3)."
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"In spite of the key roles of PIP 2 and BK channels in cell excitability and signaling, it remains unknown whether PIP 2 can directly modulate BK channel function."
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"Therefore, the sequence RKK in the cbv1 S6-S7 linker is involved in PIP 2 activation of the BK channel."
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"Previous findings demonstrated that metabolic products of PIP 2 and downstream targets such as PLC, ryanodine receptors, kinases, and free fatty acids modulate BK channel activity."
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"Indeed, using recombinant mslo1 channels expressed in Xenopus laevis oocytes, the Logothetis laboratory identified the Lys Asp Arg Asp Asp loop, which follows the so-called A segment in the slo1 RCK1 domain, as another mediator of PIP activation of slo1 channels."
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"Additionally, activation of lipid kinases via Mg-ATP increases membrane PIP 2 levels and thus modulates BK channel activity."
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"Slo1 activation by PIP 2 was linked to the presence of activating Ca 2+ and increased with increasing amounts of this divalent [ xref ]."
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"However, an essential role of the GR domain may be excluded, at least in our experimental conditions, because the truncated Slo1 channel without the GR domain can be robustly stimulated by PIP 2 when coexpressed with beta1."
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"Using both Xenopus laevis oocytes and transiently transfected HEK cells, the Hoshi laboratory aimed at addressing the role of (1) distinct gating aspects and (2) BK channel subunit composition in PIP modulation of BK channel activity."
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"Slo1 activation by PIP was linked to the presence of activating Ca and increased with increasing amounts of this divalent [13]."
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"PIP 2 clearly decreased macroscopic currents through Slo1 and Slo1 + gamma1 but increased macroscopic currents through Slo1 + beta1 and Slo1 + beta4 (XREF_FIG)."
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"The observation that native BK channels were found sensitive to exogenous PIP application raised the question of whether endogenous PIP present in physiological amounts in cells modulated BK channel function and, if so, whether such modulation could impact organ function."
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"Indeed, using recombinant mslo1 channels expressed in Xenopus laevis oocytes, the Logothetis laboratory identified the Lys 366 Asp 367 Arg 368 Asp 369 Asp 370 loop, which follows the so-called A segment in the slo1 RCK1 domain, as another mediator of PIP 2 activation of slo1 channels."
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