Multidrug resistance protein transporter and Ins(1,4,5)P₃-sensitive Ca²+-signaling involved in adenosine triphosphate export via Gq protein-coupled NK₂-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.
Sun
Jing
J
Department of Medical Research Center, School of Medicine, Fukuoka University, Japan.
Usune
Sadaharu
S
Zhao
Yumei
Y
Migita
Keisuke
K
Katsuragi
Takeshi
T
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006168:Guinea Pigs; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D008297:Male; D015288:Neurokinin A / Q000494:pharmacology / Q000502:physiology*; D011422:Propionates / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018435:ATP Binding Cassette Transporter, Subfamily B; D011422:Propionates; D011804:Quinolines; D018041:Receptors, Neurokinin-2; C059141:verlukast; D015544:Inositol 1,4,5-Trisphosphate; D015288:Neurokinin A; D000255:Adenosine Triphosphate; D043802:GTP-Binding Protein alpha Subunits, Gq-G11