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Modulation of rat atrial G protein‐coupled K + channel function by phospholipids
Author(s) -
Kim Donghee,
Bang Hyoweon
Publication year - 1999
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.1999.0059z.x
Subject(s) - chemistry , potassium channel , g protein , kir6.2 , biochemistry , protein subunit , biophysics , pharmacology , biology , receptor , gene
1 G protein‐gated K + channels (K ACh channels) in the heart and brain are activated by the βγ subunit of inhibitory G protein. Phosphatidylinositol‐4,5‐bisphosphate (PIP 2 ) has recently been reported to directly activate K ACh channels (GIRK) expressed in oocytes, as well as to support activation by the βγ subunit in the presence of Na + . We examined the effect of Na + , PIP 2 and other phospholipids on the K ACh channel to understand better their role in K ACh channel activation and modulation. 2 In atrial membrane patches, none of the phospholipids tested including PIP 2 caused activation of the K ACh channel in either the presence or the absence of 30 mM Na + . PIP 2 (3 μM) and other phospholipids (30 μM) blocked acetylcholine‐induced activation of the K ACh channel. 3 When K ACh channels were first activated with GTPγS, however, all phospholipids (100 μM) tested augmented the K ACh channel activity 1·5‐ to 2‐fold. Phosphatidylinositol‐4‐phosphate (PIP) and PIP 2 were an order of magnitude more potent than other phospholipids. The increase in K ACh channel activity was the result of a shift in the gating mode of the channel from a short‐lived to a longer‐lived open state. Such a modulatory effect was qualitatively similar to that produced by intracellular ATP. Trypsin blocked the ATP effect but not the phospholipid effect on the K ACh channel kinetics. 4 The phosphate group linked to the glycerol backbone was important for K ACh channel modulation by phospholipids. The higher potency of PIP and PIP 2 was due to the presence of inositol phosphates. 5 Intracellular Na + (30 mM) increased the frequency of K ACh channel opening ≈2‐fold if the channels were already active, but did not affect modulation by phospholipids. The effects of Na + and phospholipids on K ACh channel activity were additive. 6 A low concentration of ATP (20 μM), which had no effect on the K ACh channel by itself, potentiated the stimulatory action of phospholipids, indicating that ATP and phospholipids interacted to modulate K ACh channel function. 7 We conclude that exogenously applied PIP 2 and other phospholipids block agonist‐mediated K ACh channel activation. However, if the K ACh channel is already activated with GTPγS, phospholipids augment the existing activity by increasing the number of longer‐lived channel openings. The evidence for and against the role of PIP and PIP 2 in the stimulatory effect of ATP on the K ACh channel is presented and discussed.