Transient receptor potential melastatin 3 is a phosphoinositide-dependent ion channel

被引:49
作者
Badheka, Doreen [1 ]
Borbiro, Istvan [1 ]
Rohacs, Tibor [1 ]
机构
[1] Rutgers New Jersey Med Sch, Dept Physiol & Pharmacol, Newark, NJ 07103 USA
基金
美国国家卫生研究院;
关键词
PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; POTASSIUM CHANNELS; CA2+-DEPENDENT DESENSITIZATION; TRPV1; CHANNELS; PIP2; ACTIVATION; TRPM3; DETERMINANTS; INACTIVATION; TRANSDUCTION;
D O I
10.1085/jgp.201411336
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Phosphoinositides are emerging as general regulators of the functionally diverse transient receptor potential (TRP) ion channel family. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2) has been reported to positively regulate many TRP channels, but in several cases phosphoinositide regulation is controversial. TRP melastatin 3 (TRPM3) is a heat-activated ion channel that is also stimulated by chemical agonists, such as pregnenolone sulfate. Here, we used a wide array of approaches to determine the effects of phosphoinositides on TRPM3. We found that channel activity in excised inside-out patches decreased over time (rundown), an attribute of PI(4,5)P-2-dependent ion channels. Channel activity could be restored by application of either synthetic dioctanoyl (diC(8)) or natural arachidonyl stearyl (AASt) PI(4,5)P-2. The PI(4,5)P-2 precursor phosphatidylinositol 4-phosphate (PI(4)P) was less effective at restoring channel activity. TRPM3 currents were also restored by MgATP, an effect which was inhibited by two different phosphatidylinositol 4-kinase inhibitors, or by pretreatment with a phosphatidylinositol-specific phospholipase C (PI-PLC) enzyme, indicating that MgATP acted by generating phosphoinositides. In intact cells, reduction of PI(4,5)P-2 levels by chemically inducible phosphoinositide phosphatases or a voltage-sensitive 5'-phosphatase inhibited channel activity. Activation of PLC via muscarinic receptors also inhibited TRPM3 channel activity. Overall, our data indicate that TRPM3 is a phosphoinositide-dependent ion channel and that decreasing PI(4,5)P-2 abundance limits its activity. As all other members of the TRPM family have also been shown to require PI(4,5)P-2 for activity, our data establish PI(4,5)P-2 as a general positive cofactor of this ion channel subfamily.
引用
收藏
页码:65 / 77
页数:13
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