Alterations in an inositol phosphate code through synergistic activation of a G protein and inositol phosphate kinases

作者：Otto James C; Kelly Patrick; Chiou Shean Tai; York John D^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(40): 15653-15658.

DOI：10.1073/pnas.0705729104

• Gq
• metabolomics
• phospholipase C
• signal transduction
• G protein-coupled receptor

In mammals, many cellular stimuli evoke a response through G protein activation of phospholipase C, which results in the lipid-derived production of inositol 1,45-trisphosphate (IP(3)). Although it is well established that IP3 is converted to numerous inositol phosphates (IPs) and pyrophosphates (PP-IPs) through the action of up to six classes of inositol phosphate kinases (IPKs), it is not clear that these metabolites are influenced by G protein signaling. Here we report that activation of G alpha(q) leads to robust stimulation of IP(3) to IP(8) metabolism. To expose flux through these pathways, genetic perturbation was used to alter IP homeostasis. Coupled expression of a constitutively active G alpha(q)QL and one or more IPK gene products synergistically generated dramatic changes in the patterns of intracellular IP messengers. Many distinct IP profiles were observed through the expression of different combinations of IPKs, including changes in previously unappreciated pools of IP(5) and IP(6), two molecules widely viewed as stable metabolites. Our data link the activation of a trimeric G protein to a plethora of metabolites downstream Of IP3 and provide a framework for suggesting that cells possess the machinery to produce an IPK-dependent IP code. We imply, but do not prove, that agonist-induced alterations in such a code would theoretically be capable of enhancing signaling complexity and specificity. The essential roles for IPKs in organism development and cellular adaptation are consistent with our hypothesis that such an IP code may be relevant to signaling pathways.

• 出版日期2007-10-2