Modulation of rat atrial G protein-coupled K+ channel function by phospholipids

被引:23
作者
Kim, D [1 ]
Bang, H [1 ]
机构
[1] Finch Univ Hlth Sci Chicago Med Sch, Dept Physiol & Biophys, N Chicago, IL 60064 USA
来源
JOURNAL OF PHYSIOLOGY-LONDON | 1999年 / 517卷 / 01期
关键词
D O I
10.1111/j.1469-7793.1999.0059z.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
1. G protein-gated K+ channels (K-ACh channels) in the heart and brain are activated by the beta gamma subunit of inhibitory G protein. Phosphatidylinositol-4,5-bisphosphate (PIP2) has recently been reported to directly activate K-ACh channels (GIRK) expressed in oocytes, as well as to support activation by the beta gamma subunit in the presence of Na+. We examined the effect of Na+, PIP2 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 PIP2 caused activation of the K-ACh channel in either the presence or the absence of 30 mM Na+. PIP2 (3 mu M) and other phospholipids (30 mu M) blocked acetylcholine-induced activation of the K-ACh channel. 3. When K-ACh channels were first activated with GTP gamma S, however, all phospholipids (100 mu M) tested augmented the K-ACh channel activity 1.5- to 2-fold. Phosphatidylinositol-4-phosphate (PIP) and PIP2 mere an order of magnitude more potent than other phospholipids. The increase in K-ACh dlannel 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 nut 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 PIP2 was due to the presence of inositol phosphates. 5. Intracellular Na+ (30 mM) increased the frequency of K-ACh channel opening similar to 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 mu M), 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 PIP2 and other phospholipids block agonist-mediated K-ACh channel activation. However, if the K-ACh channel is already activated with GTP gamma S, phospholipids augment the existing activity by increasing the number of longer-lived channel openings. The evidence for and against the role of PIP and PIP2 in the stimulatory effect of ATP on the K-ACh channel is presented and discussed.
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页码:59 / 74
页数:16
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