title: Stimulation of histamine H2 receptors activates TRPC3 channels through both phospholipase C and phospholipase D.
abstract: Histamine plays an important role in many physiological functions; and a change in cytosolic Ca(2+) ([Ca(2+)](i)) may be an early signal in these processes. In the present study, we investigated the activation mechanism of TRPC3, the Canonical Transient Receptors Potential 3 Channels, by histamine via a non-capacitative Ca(2+) entry pathway. TRPC3 was transfected into HEK293 cells and the cells were treated with thapsigargin to deplete the intracellular Ca(2+) stores; re-addition of Ca(2+) initiated a capacitative Ca(2+) entry (CCE). A subsequent application of histamine evoked another Ca(2+) influx on top of the CCE signal only in the TRPC3-transfected HEK293 cells, indicating that histamine can activate TRPC3 via a non-capacitative Ca(2+) entry pathway (non-CCE). This histamine-induced non-CCE was abolished by cimitidine, a histamine H(2) receptors antagonist, but not by histamine H(1) receptor antagonists pyrilamine and diphenhydramine. KT5720, a protein kinase A (PKA) inhibitor, had no effect on the histamine-induced non-CCE. This histamine-induced non-CCE was partially reduced by U73122, a phospholipase C (PLC) inhibitor, and by butan-1-ol, a phospholipase D (PLD) inhibitor. When both PLC and PLD inhibitors were simultaneously applied, the non-CCE signal was completely abolished. Taken together, our results showed, for the first time, that histamine could activate TRPC3 via histamine H(2) receptors, and both PLC and PLD participated in this process.
authors.affiliation: Faculty of Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. kwanhy@alumni.cuhk.net
authors.forename: Hiu-Yee
authors.initials: HY
authors.lastname: Kwan
authors.forename: Ching-On
authors.initials: CO
authors.lastname: Wong
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Chen
authors.forename: Tak-Wah
authors.initials: TW
authors.lastname: Dominic Chan
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004075:Diglycerides / Q000096:biosynthesis; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D010739:Phospholipase D / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050052:TRPC Cation Channels / Q000819:agonists* / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D004075:Diglycerides; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D006632:Histamine; D017868:Cyclic AMP-Dependent Protein Kinases; D010738:Type C Phospholipases; D010739:Phospholipase D; D002118:Calcium