Multidrug resistance protein transporter and ins(1,4,5)P 3-sensitive Ca 2+-signaling involved in adenosine triphosphate export via Gq protein-coupled NK 2-receptor stimulation with neurokinin A

The purpose of this study is to identify the membrane transport machinery and cell signaling involved in the neurokinin a-inducible release of adenosine triphosphate (atp) as an autocrine/paracrine signal from cultured guinea-pig taenia coli (t. coli) smooth muscle cells (smcs). atp release evoked by neurokinin a was inhibited by l-659877,a nk 2-receptor antagonist; by modulators for ins(1,4,5)p 3-sensitive ca 2+-signaling,u-73122,thapsigargin,and 2-apb; and by w-7,a calmodulin inhibitor,and staurosporine,a protein kinase c (pkc) inhibitor,but not by wortmannin,a phosphoinositide 3-kinase inhibitor. the evoked release was suppressed by a multidrug resistance protein (mrp)-transporter inhibitors,mk-571,indomethacin,and benzbromarone,but not by cftr-inh 172,a cftr-cl - channel blocker,and α-glycyrrhetinic acid,a gap junction hemichannel blocker. neurokinin a caused a marked accumulation of ins(1,4,5)p 3 and an increase in [ca 2+]i in the cultured cells. these findings suggest that stimulation of gq/11 protein- coupled nk 2 receptor with neurokinin a caused a substantial release of atp from cultured t. coli smcs and that the evoked release may be mediated by ins(1,4,5)p 3-sensitive ca 2+-signaling,further by pkc and ca 2+/calmodulin signals,and finally by an activation of mrp transporters as the membrane device. ©2010 the japanese pharmacological society.